Journal articles: 'Neuronal cell loss'

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Fricker, Michael, Aviva M. Tolkovsky, Vilmante Borutaite, Michael Coleman, and Guy C. Brown. "Neuronal Cell Death." Physiological Reviews 98, no. 2 (April 1, 2018): 813–80. http://dx.doi.org/10.1152/physrev.00011.2017.

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Neuronal cell death occurs extensively during development and pathology, where it is especially important because of the limited capacity of adult neurons to proliferate or be replaced. The concept of cell death used to be simple as there were just two or three types, so we just had to work out which type was involved in our particular pathology and then block it. However, we now know that there are at least a dozen ways for neurons to die, that blocking a particular mechanism of cell death may not prevent the cell from dying, and that non-neuronal cells also contribute to neuronal death. We review here the mechanisms of neuronal death by intrinsic and extrinsic apoptosis, oncosis, necroptosis, parthanatos, ferroptosis, sarmoptosis, autophagic cell death, autosis, autolysis, paraptosis, pyroptosis, phagoptosis, and mitochondrial permeability transition. We next explore the mechanisms of neuronal death during development, and those induced by axotomy, aberrant cell-cycle reentry, glutamate (excitoxicity and oxytosis), loss of connected neurons, aggregated proteins and the unfolded protein response, oxidants, inflammation, and microglia. We then reassess which forms of cell death occur in stroke and Alzheimer’s disease, two of the most important pathologies involving neuronal cell death. We also discuss why it has been so difficult to pinpoint the type of neuronal death involved, if and why the mechanism of neuronal death matters, the molecular overlap and interplay between death subroutines, and the therapeutic implications of these multiple overlapping forms of neuronal death.

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Sugawara, Mitsuru, Gabriel Corfas, and M. Charles Liberman. "Influence of Supporting Cells on Neuronal Degeneration After Hair Cell Loss." Journal of the Association for Research in Otolaryngology 6, no. 2 (June 2005): 136–47. http://dx.doi.org/10.1007/s10162-004-5050-1.

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Smith, Ruben, Hinfan Chung, Sara Rundquist, Marion L. C. Maat-Schieman, Lesley Colgan, Elisabet Englund, Yong-Jian Liu, et al. "Cholinergic neuronal defect without cell loss in Huntington's disease." Human Molecular Genetics 15, no. 21 (September 20, 2006): 3119–31. http://dx.doi.org/10.1093/hmg/ddl252.

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Takács-Vellai, Krisztina, Andrew Bayci, and Tibor Vellai. "Autophagy in neuronal cell loss: a road to death." BioEssays 28, no. 11 (2006): 1126–31. http://dx.doi.org/10.1002/bies.20489.

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Abad-Rodriguez, Jose, Maria Dolores Ledesma, Katleen Craessaerts, Simona Perga, Miguel Medina, Andre Delacourte, Colin Dingwall, Bart De Strooper, and Carlos G. Dotti. "Neuronal membrane cholesterol loss enhances amyloid peptide generation." Journal of Cell Biology 167, no. 5 (December 6, 2004): 953–60. http://dx.doi.org/10.1083/jcb.200404149.

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Recent experimental and clinical retrospective studies support the view that reduction of brain cholesterol protects against Alzheimer's disease (AD). However, genetic and pharmacological evidence indicates that low brain cholesterol leads to neurodegeneration. This apparent contradiction prompted us to analyze the role of neuronal cholesterol in amyloid peptide generation in experimental systems that closely resemble physiological and pathological situations. We show that, in the hippocampus of control human and transgenic mice, only a small pool of endogenous APP and its β-secretase, BACE 1, are found in the same membrane environment. Much higher levels of BACE 1–APP colocalization is found in hippocampal membranes from AD patients or in rodent hippocampal neurons with a moderate reduction of membrane cholesterol. Their increased colocalization is associated with elevated production of amyloid peptide. These results suggest that loss of neuronal membrane cholesterol contributes to excessive amyloidogenesis in AD and pave the way for the identification of the cause of cholesterol loss and for the development of specific therapeutic strategies.

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Kranenburg, O., V. Scharnhorst, A. J. Van der Eb, and A. Zantema. "Inhibition of cyclin-dependent kinase activity triggers neuronal differentiation of mouse neuroblastoma cells." Journal of Cell Biology 131, no. 1 (October 1, 1995): 227–34. http://dx.doi.org/10.1083/jcb.131.1.227.

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Studies on the molecular mechanisms underlying neuronal differentiation are frequently performed using cell lines established from neuroblastomas. In this study we have used mouse N1E-115 neuroblastoma cells that undergo neuronal differentiation in response to DMSO. During differentiation, cyclin-dependent kinase (cdk) activities decline and phosphorylation of the retinoblastoma gene product (pRb) is lost, leading to the appearance of a pRb-containing E2F DNA-binding complex. The loss of cdk2 activity is due to a decrease in cdk2 abundance whereas loss of cdk4 activity is caused by strong association with the cdk inhibitor (CKI) p27KIP1 and concurrent loss of cdk4 phosphorylation. Moreover, neuronal differentiation can be induced by overexpression of p27KIP1 or pRb, suggesting that inhibition of cdk activity leading to loss of pRb phosphorylation, is the major determinant for neuronal differentiation.

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Oue, Hiroshi, Yasunari Miyamoto, Shinsuke Okada, Katsunori Koretake, Cha-Gyun Jung, Makoto Michikawa, and Yasumasa Akagawa. "Tooth loss induces memory impairment and neuronal cell loss in APP transgenic mice." Behavioural Brain Research 252 (September 2013): 318–25. http://dx.doi.org/10.1016/j.bbr.2013.06.015.

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Korwitz, Anne, Carsten Merkwirth, Ricarda Richter-Dennerlein, Simon E. Tröder, Hans-Georg Sprenger, Pedro M. Quirós, Carlos López-Otín, Elena I. Rugarli, and Thomas Langer. "Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria." Journal of Cell Biology 212, no. 2 (January 18, 2016): 157–66. http://dx.doi.org/10.1083/jcb.201507022.

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Proteolytic cleavage of the dynamin-like guanosine triphosphatase OPA1 in mitochondria is emerging as a central regulatory hub that determines mitochondrial morphology under stress and in disease. Stress-induced OPA1 processing by OMA1 triggersmitochondrial fragmentation, which is associated with mitophagy and apoptosis in vitro. Here, we identify OMA1 as a critical regulator of neuronal survival in vivo and demonstrate that stress-induced OPA1 processing by OMA1 promotes neuronal death and neuroinflammatory responses. Using mice lacking prohibitin membrane scaffolds as a model of neurodegeneration, we demonstrate that additional ablation of Oma1 delays neuronal loss and prolongs lifespan. This is accompanied by the accumulation of fusion-active, long OPA1 forms, which stabilize the mitochondrial genome but do not preserve mitochondrial cristae or respiratory chain supercomplex assembly in prohibitin-depleted neurons. Thus, long OPA1 forms can promote neuronal survival independently of cristae shape, whereas stress-induced OMA1 activation and OPA1 cleavage limit mitochondrial fusion and promote neuronal death.

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Tang, Damu, Isao Matsuura, Jerry H. Wang, Ki-Young Lee, and Zhong Qi. "Neuronal Cdc2-like kinase: from cell cycle to neuronal function." Biochemistry and Cell Biology 74, no. 4 (July 1, 1996): 419–29. http://dx.doi.org/10.1139/o96-046.

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Neuronal Cdc2-like kinase, Nclk, is a heterodimer of cyclin-dependent protein kinase 5 (Cdk5) and a 25-kDa essential regulatory subunit that is derived from a 35-kDa brain- and neuron-specific protein. This protein is called neuronal Cdk5 activator, p25/35nck5a. Nclk is one of the best characterized Cdc2 family kinases whose primary function is not cell cycle related. It has been suggested that this protein kinase plays important roles in neurocytoskeleton dynamics and its loss of regulation has been implicated in Alzheimer pathology. As a member of the Cdc2-like kinase family, Nclk shares many common properties with other members of the Cdc2-like kinase family. It also possesses unique characteristics that may be related to its distinct and noncell cycle related functions. The regulatory and functional properties of Nclk are reviewed in this communication.Key words: Cdc2 kinase, Cdk5, neuronal Cdk5 activator.

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Lu, Jian-Qiang, Trevor A. Steve, Matt Wheatley, and Donald W. Gross. "Immune Cell Infiltrates in Hippocampal Sclerosis: Correlation With Neuronal Loss." Journal of Neuropathology & Experimental Neurology 76, no. 3 (March 2017): 206–15. http://dx.doi.org/10.1093/jnen/nlx001.

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11

Andersen, Julie K. "Does neuronal loss in Parkinson's disease involve programmed cell death?" BioEssays 23, no. 7 (2001): 640–46. http://dx.doi.org/10.1002/bies.1089.

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Horn, Zachi, Hourinaz Behesti, and Mary E. Hatten. "N-cadherin provides a cis and trans ligand for astrotactin that functions in glial-guided neuronal migration." Proceedings of the National Academy of Sciences 115, no. 42 (September 27, 2018): 10556–63. http://dx.doi.org/10.1073/pnas.1811100115.

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Prior studies demonstrate that astrotactin (ASTN1) provides a neuronal receptor for glial-guided CNS migration. Here we report that ASTN1 binds N-cadherin (CDH2) and that the ASTN1:CDH2 interaction supports cell–cell adhesion. To test the function of ASTN1:CDH2 binding in glial-guided neuronal migration, we generated a conditional loss of Cdh2 in cerebellar granule cells and in glia. Granule cell migration was slowed in cerebellar slice cultures after a conditional loss of neuronal Cdh2, and more severe migration defects occurred after a conditional loss of glial Cdh2. Expression in granule cells of a mutant form of ASTN1 that does not bind CDH2 also slowed migration. Moreover, in vitro chimeras of granule cells and glia showed impaired neuron–glia attachment in the absence of glial, but not neuronal, Cdh2. Thus, cis and trans bindings of ASTN1 to neuronal and glial CDH2 form an asymmetric neuron–glial bridge complex that promotes glial-guided neuronal migration.

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You, Wenting, Tos T. J. M. Berendschot, Kèvin Knoops, Marc A. M. J. van Zandvoort, Carroll A. B. Webers, Chris P. M. Reutelingsperger, and Theo G. M. F. Gorgels. "Single Cell Analysis of Reversibility of the Cell Death Program in Ethanol-Treated Neuronal PC12 Cells." International Journal of Molecular Sciences 23, no. 5 (February 28, 2022): 2650. http://dx.doi.org/10.3390/ijms23052650.

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Neurodegenerative diseases are generally characterized clinically by the selective loss of a distinct subset of neurons and a slow progressive course. Mounting evidence in vivo indicates that large numbers of neurons pass through a long period of injury and dysfunction before the actual death of the cells. Whether these dying neurons can be rescued and return to a normal, functional state is uncertain. In the present study, we explored the reversibility of the neuronal cell death pathway at various stages by monitoring the dynamics of single cells with high-resolution live-cell spinning disk confocal microscopy in an in vitro neuronal cell death model. We exposed differentiated neuronal PC12 cells to ethanol as our cell death model. Results showed that exposure to 5% ethanol for 24 h induced cell death in >70% of the cells. Ethanol treatment for 3 h already induced cellular changes and damage such as reactive oxygen species generation, elevation of intracellular Ca2+ level, phosphatidylserine exposure, nuclear shrinkage, DNA damage, mitochondrial fragmentation and membrane potential loss, and retraction of neurites. These phenomena are often associated with programmed cell death. Importantly, after removing ethanol and further culturing these damaged cells in fresh culture medium, cells recovered from all these cell injuries and generated new neurites. Moreover, results indicated that this recovery was not dependent on exogenous NGF and other growth factors in the cell culture medium. Overall, our results suggest that targeting dying neurons can be an effective therapeutic strategy in neurodegenerative diseases.

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Hilton, Genell D., Bogdan A. Stoica, Kimberly R. Byrnes, and Alan I. Faden. "Roscovitine Reduces Neuronal Loss, Glial Activation, and Neurologic Deficits after Brain Trauma." Journal of Cerebral Blood Flow & Metabolism 28, no. 11 (July 9, 2008): 1845–59. http://dx.doi.org/10.1038/jcbfm.2008.75.

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Traumatic brain injury (TBI) causes both direct and delayed tissue damage. The latter is associated with secondary biochemical changes such as cell cycle activation, which leads to neuronal death, inflammation, and glial scarring. Flavopiridol—a cyclin-dependent kinase (CDK) inhibitor that is neither specific nor selective—is neuroprotective. To examine the role of more specific CDK inhibitors as potential neuroprotective agents, we studied the effects of roscovitine in TBI. Central administration of roscovitine 30 mins after injury resulted in significantly decreased lesion volume, as well as improved motor and cognitive recovery. Roscovitine attenuated neuronal death and inhibited activation of cell cycle pathways in neurons after TBI, as indicated by attenuated cyclin G1 accumulation and phosphorylation of retinoblastoma protein. Treatment also decreased microglial activation after TBI, as reflected by reductions in ED1, galectin-3, p22PHOX, and Iba-1 levels, and attenuated astrogliosis, as shown by decreased accumulation of glial fibrillary acidic protein. In primary cortical microglia and neuronal cultures, roscovitine and other selective CDK inhibitors attenuated neuronal cell death, as well as decreasing microglial activation and microglial-dependent neurotoxicity. These data support a multifactorial neuroprotective effect of cell cycle inhibition after TBI—likely related to inhibition of neuronal apoptosis, microglial-induced inflammation, and gliosis—and suggest that multiple CDKs are potentially involved in this process.

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McAvoy, Kathleen M., Hameetha Rajamohamed Sait, Galina Marsh, Michael Peterson, Taylor L. Reynolds, Jake Gagnon, Sarah Geisler, et al. "Cell-autonomous and non-cell autonomous effects of neuronal BIN1 loss in vivo." PLOS ONE 14, no. 8 (August 13, 2019): e0220125. http://dx.doi.org/10.1371/journal.pone.0220125.

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Tsuyama, Taiichi, Asako Tsubouchi, Tadao Usui, Hiromi Imamura, and Tadashi Uemura. "Mitochondrial dysfunction induces dendritic loss via eIF2α phosphorylation." Journal of Cell Biology 216, no. 3 (February 16, 2017): 815–34. http://dx.doi.org/10.1083/jcb.201604065.

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Mitochondria are key contributors to the etiology of diseases associated with neuromuscular defects or neurodegeneration. How changes in cellular metabolism specifically impact neuronal intracellular processes and cause neuropathological events is still unclear. We here dissect the molecular mechanism by which mitochondrial dysfunction induced by Prel aberrant function mediates selective dendritic loss in Drosophila melanogaster class IV dendritic arborization neurons. Using in vivo ATP imaging, we found that neuronal cellular ATP levels during development are not correlated with the progression of dendritic loss. We searched for mitochondrial stress signaling pathways that induce dendritic loss and found that mitochondrial dysfunction is associated with increased eIF2α phosphorylation, which is sufficient to induce dendritic pathology in class IV arborization neurons. We also observed that eIF2α phosphorylation mediates dendritic loss when mitochondrial dysfunction results from other genetic perturbations. Furthermore, mitochondrial dysfunction induces translation repression in class IV neurons in an eIF2α phosphorylation-dependent manner, suggesting that differential translation attenuation among neuron subtypes is a determinant of preferential vulnerability.

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Kreutzfeldt, Mario, Andreas Bergthaler, Marylise Fernandez, Wolfgang Brück, Karin Steinbach, Mariann Vorm, Roland Coras, et al. "Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell–mediated dendrite and synapse loss." Journal of Experimental Medicine 210, no. 10 (September 2, 2013): 2087–103. http://dx.doi.org/10.1084/jem.20122143.

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Neurons are postmitotic and thus irreplaceable cells of the central nervous system (CNS). Accordingly, CNS inflammation with resulting neuronal damage can have devastating consequences. We investigated molecular mediators and structural consequences of CD8+ T lymphocyte (CTL) attack on neurons in vivo. In a viral encephalitis model in mice, disease depended on CTL-derived interferon-γ (IFN-γ) and neuronal IFN-γ signaling. Downstream STAT1 phosphorylation and nuclear translocation in neurons were associated with dendrite and synapse loss (deafferentation). Analogous molecular and structural alterations were also found in human Rasmussen encephalitis, a CTL-mediated human autoimmune disorder of the CNS. Importantly, therapeutic intervention by IFN-γ blocking antibody prevented neuronal deafferentation and clinical disease without reducing CTL responses or CNS infiltration. These findings identify neuronal IFN-γ signaling as a novel target for neuroprotective interventions in CTL-mediated CNS disease.

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Moon, Jeong-mi, Lijun Xu, and Rona G. Giffard. "Inhibition of microRNA-181 Reduces Forebrain Ischemia-Induced Neuronal Loss." Journal of Cerebral Blood Flow & Metabolism 33, no. 12 (September 4, 2013): 1976–82. http://dx.doi.org/10.1038/jcbfm.2013.157.

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MicroRNA (miRNA), miR-181a, is enriched in the brain, and inhibition of miR-181a reduced astrocyte death in vitro and infarct volume after stroke in vivo. This study investigated the role of miR-181a in neuronal injury in vitro and hippocampal neuronal loss in vivo after forebrain ischemia. miR-181a levels were altered by transfection with mimic or antagomir. N2a cells subjected to serum deprivation and oxidative stress showed less cell death when miR-181a was reduced and increased death when miR-181a increased; protection was associated with increased Bcl-2 protein. In contrast, transfected primary neurons did not show altered levels of cell death when miR-181a levels changed. Naive male rats and rats stereotactically infused with miR-181a antagomir or control were subjected to forebrain ischemia and cornus ammonis (CA)1 neuronal survival and protein levels were assessed. Forebrain ischemia increased miR-181a expression and decreased Bcl-2 protein in the hippocampal CA1 region. miR-181a antagomir reduced miR-181a levels, reduced CA1 neuronal loss, increased Bcl-2 protein, and significantly prevented the decrease of glutamate transporter 1. Thus, miR-181a antagomir reduced evidence of astrocyte dysfunction and increased CA1 neuronal survival. miR-181a inhibition is thus a potential target in the setting of forebrain or global cerebral ischemia as well as focal ischemia.

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Cross, J. L., B. P. Meloni, A. J. Bakker, S. Lee, and N. W. Knuckey. "Modes of Neuronal Calcium Entry and Homeostasis following Cerebral Ischemia." Stroke Research and Treatment 2010 (2010): 1–9. http://dx.doi.org/10.4061/2010/316862.

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One of the major instigators leading to neuronal cell death and brain damage following cerebral ischemia is calcium dysregulation. The neuron's inability to maintain calcium homeostasis is believed to be a result of increased calcium influx and impaired calcium extrusion across the plasma membrane. The need to better understand the cellular and biochemical mechanisms of calcium dysregulation contributing to neuronal loss following stroke/cerebral ischemia is essential for the development of new treatments in order to reduce ischemic brain injury. The aim of this paper is to provide a concise overview of the various calcium influx pathways in response to ischemia and how neuronal cells attempts to overcome this calcium overload.

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Kume, Akito, Akira Takahashi, and Yoshio Hashizume. "Neuronal cell loss of the striatonigral system in multiple system atrophy." Journal of the Neurological Sciences 117, no. 1-2 (July 1993): 33–40. http://dx.doi.org/10.1016/0022-510x(93)90151-n.

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Sandberg, G. D., K. Wong, A. L. Morrison, C. H. Colegial, H. Mena, and R. Schiffmann. "NEUROPATHOLOGIC CLUES TO LAMINAR NEURONAL CELL LOSS IN NEURONOPATHIC GAUCHER DISEASE." Journal of Neuropathology and Experimental Neurology 57, no. 5 (May 1998): 484. http://dx.doi.org/10.1097/00005072-199805000-00071.

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Labouesse, M., E. Hartwieg, and H. R. Horvitz. "The Caenorhabditis elegans LIN-26 protein is required to specify and/or maintain all non-neuronal ectodermal cell fates." Development 122, no. 9 (September 1, 1996): 2579–88. http://dx.doi.org/10.1242/dev.122.9.2579.

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The C. elegans gene lin-26, which encodes a presumptive zinc-finger transcription factor, is required for hypodermal cells to acquire their proper fates. Here we show that lin-26 is expressed not only in all hypodermal cells but also in all glial-like cells. During asymmetric cell divisions that generate a neuronal cell and a non-neuronal cell, LIN-26 protein is symmetrically segregated and then lost from the neuronal cell. Expression in glial-like cells (socket and sheath cells) is biologically important, as some of these neuronal support cells die or seem sometimes to be transformed to neuron-like cells in embryos homozygous for strong loss-of-function mutations. In addition, most of these glial-like cells are structurally and functionally defective in animals carrying the weak loss-of-function mutation lin-26(n156). lin-26 mutant phenotypes and expression patterns together suggest that lin-26 is required to specify and/or maintain the fates not only of hypodermal cells but also of all other non-neuronal ectodermal cells in C. elegans. We speculate that lin-26 acts by repressing the expression of neuronal-specific genes in non-neuronal cells.

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Dermaut, Bart, Koenraad K. Norga, Artur Kania, Patrik Verstreken, Hongling Pan, Yi Zhou, Patrick Callaerts, and Hugo J. Bellen. "Aberrant lysosomal carbohydrate storage accompanies endocytic defects and neurodegeneration in Drosophila benchwarmer." Journal of Cell Biology 170, no. 1 (July 4, 2005): 127–39. http://dx.doi.org/10.1083/jcb.200412001.

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Lysosomal storage is the most common cause of neurodegenerative brain disease in preadulthood. However, the underlying cellular mechanisms that lead to neuronal dysfunction are unknown. Here, we report that loss of Drosophila benchwarmer (bnch), a predicted lysosomal sugar carrier, leads to carbohydrate storage in yolk spheres during oogenesis and results in widespread accumulation of enlarged lysosomal and late endosomal inclusions. At the bnch larval neuromuscular junction, we observe similar inclusions and find defects in synaptic vesicle recycling at the level of endocytosis. In addition, loss of bnch slows endosome-to-lysosome trafficking in larval garland cells. In adult bnch flies, we observe age-dependent synaptic dysfunction and neuronal degeneration. Finally, we find that loss of bnch strongly enhances tau neurotoxicity in a dose-dependent manner. We hypothesize that, in bnch, defective lysosomal carbohydrate efflux leads to endocytic defects with functional consequences in synaptic strength, neuronal viability, and tau neurotoxicity.

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Liu, Chunyi, Mei Mei, Qiuling Li, Peristera Roboti, Qianqian Pang, Zhengzhou Ying, Fei Gao, Martin Lowe, and Shilai Bao. "Loss of the golgin GM130 causes Golgi disruption, Purkinje neuron loss, and ataxia in mice." Proceedings of the National Academy of Sciences 114, no. 2 (December 27, 2016): 346–51. http://dx.doi.org/10.1073/pnas.1608576114.

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The Golgi apparatus lies at the heart of the secretory pathway where it is required for secretory trafficking and cargo modification. Disruption of Golgi architecture and function has been widely observed in neurodegenerative disease, but whether Golgi dysfunction is causal with regard to the neurodegenerative process, or is simply a manifestation of neuronal death, remains unclear. Here we report that targeted loss of the golgin GM130 leads to a profound neurological phenotype in mice. Global KO of mouse GM130 results in developmental delay, severe ataxia, and postnatal death. We further show that selective deletion of GM130 in neurons causes fragmentation and defective positioning of the Golgi apparatus, impaired secretory trafficking, and dendritic atrophy in Purkinje cells. These cellular defects manifest as reduced cerebellar size and Purkinje cell number, leading to ataxia. Purkinje cell loss and ataxia first appear during postnatal development but progressively worsen with age. Our data therefore indicate that targeted disruption of the mammalian Golgi apparatus and secretory traffic results in neuronal degeneration in vivo, supporting the view that Golgi dysfunction can play a causative role in neurodegeneration.

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Sasaki, Shinji, Daisuke Mori, Kazuhito Toyo-oka, Amy Chen, Lisa Garrett-Beal, Masami Muramatsu, Shuji Miyagawa, et al. "Complete Loss of Ndel1 Results in Neuronal Migration Defects and Early Embryonic Lethality." Molecular and Cellular Biology 25, no. 17 (September 1, 2005): 7812–27. http://dx.doi.org/10.1128/mcb.25.17.7812-7827.2005.

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ABSTRACT Regulation of cytoplasmic dynein and microtubule dynamics is crucial for both mitotic cell division and neuronal migration. NDEL1 was identified as a protein interacting with LIS1, the protein product of a gene mutated in the lissencephaly. To elucidate NDEL1 function in vivo, we generated null and hypomorphic alleles of Ndel1 in mice by targeted gene disruption. Ndel1 −/− mice were embryonic lethal at the peri-implantation stage like null mutants of Lis1 and cytoplasmic dynein heavy chain. In addition, Ndel1 −/− blastocysts failed to grow in culture and exhibited a cell proliferation defect in inner cell mass. Although Ndel1 +/− mice displayed no obvious phenotypes, further reduction of NDEL1 by making null/hypomorph compound heterozygotes (Ndel1 cko/− ) resulted in histological defects consistent with mild neuronal migration defects. Double Lis1 cko/+ -Ndel1 +/− mice or Lis1 +/− -Ndel1 +/− mice displayed more severe neuronal migration defects than Lis1 cko/+ -Ndel1 +/ + mice or Lis1 +/− -Ndel1 +/+ mice, respectively. We demonstrated distinct abnormalities in microtubule organization and similar defects in the distribution of β-COP-positive vesicles (to assess dynein function) between Ndel1 or Lis1-null MEFs, as well as similar neuronal migration defects in Ndel1- or Lis1-null granule cells. Rescue of these defects in mouse embryonic fibroblasts and granule cells by overexpressing LIS1, NDEL1, or NDE1 suggest that NDEL1, LIS1, and NDE1 act in a common pathway to regulate dynein but each has distinct roles in the regulation of microtubule organization and neuronal migration.

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Etienne, Pierre, Yves Robitaille, Serge Gauthier, and N. P. V. Nair. "Nucleus basalis neuronal loss and neuritic plaques in advanced Alzheimer's disease." Canadian Journal of Physiology and Pharmacology 64, no. 3 (March 1, 1986): 318–24. http://dx.doi.org/10.1139/y86-052.

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All our advanced severe cases of Alzheimer's disease had dramatic cholinergic cell loss in the basal forebrain, even after correction for cell or nucleolus shrinkage. We examined the relation between cell loss in the various subdivisions of the nucleus basalis of Meynert and plaque counts in corresponding and noncorresponding projection areas. This relation was not interpretable because of the ambiguity in the data.

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Mines, Marjelo A., Eleonore Beurel, and Richard S. Jope. "Regulation of Cell Survival Mechanisms in Alzheimer's Disease by Glycogen Synthase Kinase-3." International Journal of Alzheimer's Disease 2011 (2011): 1–11. http://dx.doi.org/10.4061/2011/861072.

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A pivotal role has emerged for glycogen synthase kinase-3 (GSK3) as an important contributor to Alzheimer's disease pathology. Evidence for the involvement of GSK3 in Alzheimer's disease pathology and neuronal loss comes from studies of GSK3 overexpression, GSK3 localization studies, multiple relationships between GSK3 and amyloid β-peptide (Aβ), interactions between GSK3 and the microtubule-associated tau protein, and GSK3-mediated apoptotic cell death. Apoptotic signaling proceeds by either an intrinsic pathway or an extrinsic pathway. GSK3 is well established to promote intrinsic apoptotic signaling induced by many insults, several of which may contribute to neuronal loss in Alzheimer's disease. Particularly important is evidence that GSK3 promotes intrinsic apoptotic signaling induced by Aβ. GSK3 appears to promote intrinsic apoptotic signaling by modulating proteins in the apoptosis signaling pathway and by modulating transcription factors that regulate the expression of proteins involved in apoptosis. Thus, GSK3 appears to contribute to several neuropathological mechanisms in Alzheimer's disease, including apoptosis-mediated neuronal loss.

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Nicotera, Pierluigi, and Stuart A. Lipton. "Excitotoxins in Neuronal Apoptosis and Necrosis." Journal of Cerebral Blood Flow & Metabolism 19, no. 6 (June 1999): 583–91. http://dx.doi.org/10.1097/00004647-199906000-00001.

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Neuronal loss is common to many neurodegenerative diseases. Although necrosis is a common histopathologic feature observed in neuropathologic conditions, evidence is increasing that apoptosis can significantly contribute to neuronal demise. The prevalence of either type of cell death, apoptosis or necrosis, and the relevance for the progression of disease is still unclear. The debate on the occurrence and prevalence of one or the other type of death in pathologic conditions such as stroke or neurotoxic injury may in part be resolved by the proposal that different types of cell death within a tissue reflect either partial or complete execution of a common death program. Apoptosis is an active process of cell destruction, characterized morphologically by cell shrinkage, chromatin aggregation with extensive genomic fragmentation, and nuclear pyknosis. In contrast, necrosis is characterized by cell swelling, linked to rapid energy loss, and generalized disruption of ionic and internal homeostasis. This swiftly leads to membrane lysis, release of intracellular constituents that evoke a local inflammatory reaction, edema, and injury to the surrounding tissue. During the past few years, our laboratories have studied the signals and mechanisms responsible for induction or prevention of apoptosis/necrosis in neuronal injury and this is the subject of this review.

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Shindler, Kenneth S., Yangtai Guan, Elvira Ventura, Jean Bennett, and Abdolmohamad Rostami. "Retinal ganglion cell loss induced by acute optic neuritis in a relapsing model of multiple sclerosis." Multiple Sclerosis Journal 12, no. 5 (September 2006): 526–32. http://dx.doi.org/10.1177/1352458506070629.

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Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are marked by inflammatory demyelinating lesions throughout the central nervous system, including optic nerve. Neuronal loss also occurs in MS and EAE lesions, but it is not known whether neuronal loss occurs secondary to inflammation, or as a primary process. In the current study, the relationship of inflammation to retinal ganglion cell (RGC) loss during acute optic neuritis is examined. RGCs were labelled with Flourogold, and EAE was induced in SJL/J mice by immunization with proteolipid protein peptide 139- 151 (PLP). At various time points, RGCs were counted and optic nerves were examined for inflammatory cell infiltrates. No optic neuritis was detected prior to day 9 following immunization. Incidence of optic neuritis was 30% at day 9 and increased to over 70% by day 11, remaining high through day 18. In contrast, no RGC loss was detected in eyes with optic neuritis until day 14. A 43.1% reduction in RGC numbers at day 14 increased to 50.8% by day 18. No RGC loss occurred in eyes without optic neuritis. The fact that inflammation precedes RGC loss suggests that neuronal loss during optic neuritis occurs secondary to the inflammatory process.

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Kennedy, Peter G. E., Woro George, and Xiaoli Yu. "The Possible Role of Neural Cell Apoptosis in Multiple Sclerosis." International Journal of Molecular Sciences 23, no. 14 (July 8, 2022): 7584. http://dx.doi.org/10.3390/ijms23147584.

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The etiology of multiple sclerosis (MS), a demyelinating disease affecting the central nervous system (CNS), remains obscure. Although apoptosis of oligodendrocytes and neurons has been observed in MS lesions, the contribution of this cell death process to disease pathogenesis remains controversial. It is usually considered that MS-associated demyelination and axonal degeneration result from neuroinflammation and an autoimmune process targeting myelin proteins. However, experimental data indicate that oligodendrocyte and/or neuronal cell death may indeed precede the development of inflammation and autoimmunity. These findings raise the question as to whether neural cell apoptosis is the key event initiating and/or driving the pathological cascade, leading to clinical functional deficits in MS. Similarly, regarding axonal damage, a key pathological feature of MS lesions, the roles of inflammation-independent and cell autonomous neuronal processes need to be further explored. While oligodendrocyte and neuronal loss in MS may not necessarily be mutually exclusive, particular attention should be given to the role of neuronal apoptosis in the development of axonal loss. If proven, MS could be viewed primarily as a neurodegenerative disease accompanied by a secondary neuroinflammatory and autoimmune process.

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Lee, Dong Gi, Young-Kwang Kim, and Kwang-Hyun Baek. "The bHLH Transcription Factors in Neural Development and Therapeutic Applications for Neurodegenerative Diseases." International Journal of Molecular Sciences 23, no. 22 (November 11, 2022): 13936. http://dx.doi.org/10.3390/ijms232213936.

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The development of functional neural circuits in the central nervous system (CNS) requires the production of sufficient numbers of various types of neurons and glial cells, such as astrocytes and oligodendrocytes, at the appropriate periods and regions. Hence, severe neuronal loss of the circuits can cause neurodegenerative diseases such as Huntington’s disease (HD), Parkinson’s disease (PD), Alzheimer’s disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Treatment of such neurodegenerative diseases caused by neuronal loss includes some strategies of cell therapy employing stem cells (such as neural progenitor cells (NPCs)) and gene therapy through cell fate conversion. In this report, we review how bHLH acts as a regulator in neuronal differentiation, reprogramming, and cell fate determination. Moreover, several different researchers are conducting studies to determine the importance of bHLH factors to direct neuronal and glial cell fate specification and differentiation. Therefore, we also investigated the limitations and future directions of conversion or transdifferentiation using bHLH factors.

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López-González del Rey, N., J. Blesa, and J. A. Obeso. "Determinants of selective neuronal vulnerability in Parkinson's disease." ANALES RANM 138, no. 138(02) (August 31, 2021): 114–23. http://dx.doi.org/10.32440/ar.2021.138.02.rev01.

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Parkinson´s disease (PD) is the second most frequent neurodegenerative disease affecting the population older than 65 years old. This incidence will greatly increase due to the progressive aging of the population in the coming years. PD diagnosis is made when there is a 50-60% dopaminergic cell loss in the substantia nigra pars compacta (SNc) and the striatal dopamine loss reaches around 70-80%, coinciding with the onset of classical parkinsonian motor signs: tremor, rigidity and slowness of movement. A significant proportion of patients present non-motor symptoms, generally associated to disfunction of non-dopaminergic regions, which can appear before, around or after diagnosis (10-15 years). Therefore, in PD both dopaminergic and non-dopaminergic groups are affected, but the motor manifestations are the main reason for consultation and causes the greatest disability for many years. There is a large heterogeneity within dopaminergic neural groups in terms of morphology, metabolism, molecular pattern, protein accumulation, inflammation levels, protein expression, etc. In this review we discuss different factors that could explain the special vulnerability of certain dopaminergic neurons in the SNc. Knowledge on the mechanisms and underlying factors of this selective vulnerability of the ventrolateral dopaminergic neuros of the SNc is essential for developing neuromodulatory and/or neuroprotective therapies, leading in turn to halt or modify the neurodegenerative process in PD.

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Chao, C. C., T. W. Molitor, and S. Hu. "Neuroprotective role of IL-4 against activated microglia." Journal of Immunology 151, no. 3 (August 1, 1993): 1473–81. http://dx.doi.org/10.4049/jimmunol.151.3.1473.

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Abstract Microglia have been proposed to play a pathogenetic role in immunologically mediated neurodegenerative diseases. In our study, using microglial/neuronal cell cocultures primed with IFN-gamma, we found that both LPS and TNF-alpha triggered neuronal cell injury (impairment of gamma-aminobutyric acid uptake and neuronal loss) via a nitric oxide mechanism. Pretreatment of cell cocultures with IL-4, an immunosuppressive cytokine, prevented, in a dose-dependent manner, neuronal cell injury induced by activated microglia. The mechanism by which IL-4 exerts its neuroprotective effect was found to involve the inhibition of IFN-gamma priming of microglia with a subsequent decrease in the production of TNF-alpha and nitric oxide.

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Ünal-Çevik, Isın, Münire Kılınç, Yasemin Gürsoy-Özdemir, Gunfer Gurer, and Turgay Dalkara. "Loss of NeuN immunoreactivity after cerebral ischemia does not indicate neuronal cell loss: a cautionary note." Brain Research 1015, no. 1-2 (July 2004): 169–74. http://dx.doi.org/10.1016/j.brainres.2004.04.032.

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White, David T., Sumitra Sengupta, Meera T. Saxena, Qingguo Xu, Justin Hanes, Ding Ding, Hongkai Ji, and Jeff S. Mumm. "Immunomodulation-accelerated neuronal regeneration following selective rod photoreceptor cell ablation in the zebrafish retina." Proceedings of the National Academy of Sciences 114, no. 18 (April 17, 2017): E3719—E3728. http://dx.doi.org/10.1073/pnas.1617721114.

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Müller glia (MG) function as inducible retinal stem cells in zebrafish, completely repairing the eye after damage. The innate immune system has recently been shown to promote tissue regeneration in which classic wound-healing responses predominate. However, regulatory roles for leukocytes during cellular regeneration—i.e., selective cell-loss paradigms akin to degenerative disease—are less well defined. To investigate possible roles innate immune cells play during retinal cell regeneration, we used intravital microscopy to visualize neutrophil, macrophage, and retinal microglia responses to induced rod photoreceptor apoptosis. Neutrophils displayed no reactivity to rod cell loss. Peripheral macrophage cells responded to rod cell loss, as evidenced by morphological transitions and increased migration, but did not enter the retina. Retinal microglia displayed multiple hallmarks of immune cell activation: increased migration, translocation to the photoreceptor cell layer, proliferation, and phagocytosis of dying cells. To test function during rod cell regeneration, we coablated microglia and rod cells or applied immune suppression and quantified the kinetics of (i) rod cell clearance, (ii) MG/progenitor cell proliferation, and (iii) rod cell replacement. Coablation and immune suppressants applied before cell loss caused delays in MG/progenitor proliferation rates and slowed the rate of rod cell replacement. Conversely, immune suppressants applied after cell loss had been initiated led to accelerated photoreceptor regeneration kinetics, possibly by promoting rapid resolution of an acute immune response. Our findings suggest that microglia control MG responsiveness to photoreceptor loss and support the development of immune-targeted therapeutic strategies for reversing cell loss associated with degenerative retinal conditions.

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Hülskötter, Kirsten, Fred Lühder, Alexander Flügel, Vanessa Herder, and Wolfgang Baumgärtner. "Tamoxifen Application Is Associated with Transiently Increased Loss of Hippocampal Neurons following Virus Infection." International Journal of Molecular Sciences 22, no. 16 (August 6, 2021): 8486. http://dx.doi.org/10.3390/ijms22168486.

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Tamoxifen is frequently used in murine knockout systems with CreER/LoxP. Besides possible neuroprotective effects, tamoxifen is described as having a negative impact on adult neurogenesis. The present study investigated the effect of a high-dose tamoxifen application on Theiler’s murine encephalomyelitis virus (TMEV)-induced hippocampal damage. Two weeks after TMEV infection, 42% of the untreated TMEV-infected mice were affected by marked inflammation with neuronal loss, whereas 58% exhibited minor inflammation without neuronal loss. Irrespective of the presence of neuronal loss, untreated mice lacked TMEV antigen expression within the hippocampus at 14 days post-infection (dpi). Interestingly, tamoxifen application 0, 2 and 4, or 5, 7 and 9 dpi decelerated virus elimination and markedly increased neuronal loss to 94%, associated with increased reactive astrogliosis at 14 dpi. T cell infiltration, microgliosis and expression of water channels were similar within the inflammatory lesions, regardless of tamoxifen application. Applied at 0, 2 and 4 dpi, tamoxifen had a negative impact on the number of doublecortin (DCX)-positive cells within the dentate gyrus (DG) at 14 dpi, without a long-lasting effect on neuronal loss at 147 dpi. Thus, tamoxifen application during a TMEV infection is associated with transiently increased neuronal loss in the hippocampus, increased reactive astrogliosis and decreased neurogenesis in the DG.

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Brown, K. L., J. Brown, D. L. Ritchie, J. Sales, and J. R. Fraser. "Fetal cell grafts provide long-term protection against scrapie induced neuronal loss." Neuroreport 12, no. 1 (January 2001): 77–82. http://dx.doi.org/10.1097/00001756-200101220-00023.

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Rajamohamed Sait, Hameetha Banu, Kathleen Mcavoy, Galina Marsh, Michael Peterson, Taylor L. Reynolds, Jake Gagnon, Sarah Geisler, Chris Roberts, Richard Ransohoff, and Andrea Crotti. "P1-129: CELL-AUTONOMOUS AND EFFECTS OF NEURONAL BIN1 LOSS IN VIVO." Alzheimer's & Dementia 15 (July 2019): P285. http://dx.doi.org/10.1016/j.jalz.2019.06.684.

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Song, Dae-Yong, Ha-Nul Yu, Chae-Ri Park, Jin-Sook Lee, Ji-Yong Lee, Byung-Gu Park, Ran-Sook Woo, Jung-Tae Han, Byung-Pil Cho, and Tai-Kyoung Baik. "Down-regulation of microglial activity attenuates axotomized nigral dopaminergic neuronal cell loss." BMC Neuroscience 14, no. 1 (2013): 112. http://dx.doi.org/10.1186/1471-2202-14-112.

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Qi, Xin. "eIF2α links mitochondrial dysfunction to dendritic degeneration." Journal of Cell Biology 216, no. 3 (February 16, 2017): 555–57. http://dx.doi.org/10.1083/jcb.201701062.

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Although mitochondrial dysfunction has been associated with dendritic pathology in many neuronal types, how mitochondrial impairment causes the vulnerability of neuronal subtypes remains unknown. In this issue, Tsuyama et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201604065) identify eIF2α phosphorylation as a critical regulator of mitochondrial dysfunction-mediated selective dendritic loss in Drosophila neurons.

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Cartarozzi, Luciana Politti, Matheus Perez, Frank Kirchhoff, and Alexandre Leite Rodrigues de Oliveira. "Role of MHC-I Expression on Spinal Motoneuron Survival and Glial Reactions Following Ventral Root Crush in Mice." Cells 8, no. 5 (May 21, 2019): 483. http://dx.doi.org/10.3390/cells8050483.

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Lesions to the CNS/PNS interface are especially severe, leading to elevated neuronal degeneration. In the present work, we establish the ventral root crush model for mice, and demonstrate the potential of such an approach, by analyzing injury evoked motoneuron loss, changes of synaptic coverage and concomitant glial responses in β2-microglobulin knockout mice (β2m KO). Young adult (8–12 weeks old) C57BL/6J (WT) and β2m KO mice were submitted to a L4–L6 ventral roots crush. Neuronal survival revealed a time-dependent motoneuron-like cell loss, both in WT and β2m KO mice. Along with neuronal loss, astrogliosis increased in WT mice, which was not observed in β2m KO mice. Microglial responses were more pronounced during the acute phase after lesion and decreased over time, in WT and KO mice. At 7 days after lesion β2m KO mice showed stronger Iba-1+ cell reaction. The synaptic inputs were reduced over time, but in β2m KO, the synaptic loss was more prominent between 7 and 28 days after lesion. Taken together, the results herein demonstrate that ventral root crushing in mice provides robust data regarding neuronal loss and glial reaction. The retrograde reactions after injury were altered in the absence of functional MHC-I surface expression.

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Putcha, Girish V., Mohanish Deshmukh, and Eugene M. Johnson. "Inhibition of Apoptotic Signaling Cascades Causes Loss of Trophic Factor Dependence during Neuronal Maturation." Journal of Cell Biology 149, no. 5 (May 29, 2000): 1011–18. http://dx.doi.org/10.1083/jcb.149.5.1011.

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During development, neurons are acutely dependent on target-derived trophic factors for survival. This dependence on trophic support decreases dramatically with maturation in several neuronal populations, including sympathetic neurons. Analyses of nerve growth factor deprivation in immature and mature sympathetic neurons indicate that maturation aborts the cell death pathway at a point that is mechanistically indistinguishable from Bax deletion. However, neither the mRNA nor protein level of BAX changes with neuronal maturation. Therefore, BAX must be regulated posttranslationally in mature neurons. Nerve growth factor deprivation in immature sympathetic neurons induces two parallel processes: (a) a protein synthesis–dependent, caspase-independent translocation of BAX from the cytosol to mitochondria, followed by mitochondrial membrane integration and loss of cytochrome c; and (b) the development of competence-to-die, which requires neither macromolecular synthesis nor BAX expression. Activation of both signaling pathways is required for caspase activation and apoptosis in immature sympathetic neurons. In contrast, nerve growth factor withdrawal in mature sympathetic neurons did not induce the translocation of either BAX or cytochrome c. Moreover, mature neurons did not develop competence-to-die with cytoplasmic accumulation of cytochrome c. Therefore, inhibition of both BAX-dependent cytochrome c release and the development of competence-to-die contributed to the loss of trophic factor dependence associated with neuronal maturation.

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van Olst, Lynn, Carla Rodriguez-Mogeda, Carmen Picon, Svenja Kiljan, Rachel E. James, Alwin Kamermans, Susanne M. A. van der Pol, et al. "Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration." Acta Neuropathologica 141, no. 6 (March 29, 2021): 881–99. http://dx.doi.org/10.1007/s00401-021-02293-4.

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AbstractMeningeal inflammation strongly associates with demyelination and neuronal loss in the underlying cortex of progressive MS patients, thereby contributing significantly to clinical disability. However, the pathological mechanisms of meningeal inflammation-induced cortical pathology are still largely elusive. By extensive analysis of cortical microglia in post-mortem progressive MS tissue, we identified cortical areas with two MS-specific microglial populations, termed MS1 and MS2 cortex. The microglial population in MS1 cortex was characterized by a higher density and increased expression of the activation markers HLA class II and CD68, whereas microglia in MS2 cortex showed increased morphological complexity and loss of P2Y12 and TMEM119 expression. Interestingly, both populations associated with inflammation of the overlying meninges and were time-dependently replicated in an in vivo rat model for progressive MS-like chronic meningeal inflammation. In this recently developed animal model, cortical microglia at 1-month post-induction of experimental meningeal inflammation resembled microglia in MS1 cortex, and microglia at 2 months post-induction acquired a MS2-like phenotype. Furthermore, we observed that MS1 microglia in both MS cortex and the animal model were found closely apposing neuronal cell bodies and to mediate pre-synaptic displacement and phagocytosis, which coincided with a relative sparing of neurons. In contrast, microglia in MS2 cortex were not involved in these synaptic alterations, but instead associated with substantial neuronal loss. Taken together, our results show that in response to meningeal inflammation, microglia acquire two distinct phenotypes that differentially associate with neurodegeneration in the progressive MS cortex. Furthermore, our in vivo data suggests that microglia initially protect neurons from meningeal inflammation-induced cell death by removing pre-synapses from the neuronal soma, but eventually lose these protective properties contributing to neuronal loss.

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Kimura, Tetsuya, Tetsuya Fukuda, Naruhiko Sahara, Shunji Yamashita, Miyuki Murayama, Tatsuya Mizoroki, Yuji Yoshiike, et al. "Aggregation of Detergent-insoluble Tau Is Involved in Neuronal Loss but Not in Synaptic Loss." Journal of Biological Chemistry 285, no. 49 (October 4, 2010): 38692–99. http://dx.doi.org/10.1074/jbc.m110.136630.

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Hu, Zhiqiang, and Jian Tu. "The Roads to Mitochondrial Dysfunction in a Rat Model of Posttraumatic Syringomyelia." BioMed Research International 2015 (2015): 1–15. http://dx.doi.org/10.1155/2015/831490.

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The pathophysiology of posttraumatic syringomyelia is incompletely understood. We examined whether local ischemia occurs after spinal cord injury. If so, whether it causes neuronal mitochondrial dysfunction and depletion, and subsequent energy metabolism impairment results in cell starvation of energy and even cell death, contributing to the enlargement of the cavity. Local blood flow was measured in a rat model of posttraumatic syringomyelia that had received injections of quisqualic acid and kaolin. We found an86±11% reduction of local blood flow at C8 where a cyst formed at 6 weeks after syrinx induction procedure(P<0.05), and no difference in blood flow rate between the laminectomy and intact controls. Electron microscopy confirmed irreversible neuronal mitochondrion depletion surrounding the cyst, but recoverable mitochondrial loses in laminectomy rats. Profound energy loss quantified in the spinal cord of syrinx animals, and less ATP and ADP decline observed in laminectomy rats. Our findings demonstrate that an excitotoxic injury induces local ischemia in the spinal cord and results in neuronal mitochondrial depletion, and profound ATP loss, contributing to syrinx enlargement. Ischemia did not occur following laminectomy induced trauma in which mitochondrial loss and decline in ATP were reversible. This confirms excitotoxic injury contributing to the pathology of posttraumatic syringomyelia.

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Bertan, Fabio, Lena Wischhof, Liudmila Sosulina, Manuel Mittag, Dennis Dalügge, Alessandra Fornarelli, Fabrizio Gardoni, et al. "Loss of Ryanodine Receptor 2 impairs neuronal activity-dependent remodeling of dendritic spines and triggers compensatory neuronal hyperexcitability." Cell Death & Differentiation 27, no. 12 (July 8, 2020): 3354–73. http://dx.doi.org/10.1038/s41418-020-0584-2.

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AbstractDendritic spines are postsynaptic domains that shape structural and functional properties of neurons. Upon neuronal activity, Ca2+ transients trigger signaling cascades that determine the plastic remodeling of dendritic spines, which modulate learning and memory. Here, we study in mice the role of the intracellular Ca2+ channel Ryanodine Receptor 2 (RyR2) in synaptic plasticity and memory formation. We demonstrate that loss of RyR2 in pyramidal neurons of the hippocampus impairs maintenance and activity-evoked structural plasticity of dendritic spines during memory acquisition. Furthermore, post-developmental deletion of RyR2 causes loss of excitatory synapses, dendritic sparsification, overcompensatory excitability, network hyperactivity and disruption of spatially tuned place cells. Altogether, our data underpin RyR2 as a link between spine remodeling, circuitry dysfunction and memory acquisition, which closely resemble pathological mechanisms observed in neurodegenerative disorders.

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Cohen-Gadol, Aaron A., Jullie W. Pan, Jung H. Kim, Dennis D. Spencer, and Hoby H. Hetherington. "Mesial temporal lobe epilepsy: a proton magnetic resonance spectroscopy study and a histopathological analysis." Journal of Neurosurgery 101, no. 4 (October 2004): 613–20. http://dx.doi.org/10.3171/jns.2004.101.4.0613.

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Object. Proton magnetic resonance (MR) spectroscopy imaging of the ratio of N-acetylaspartate (NAA) to creatine (Cr) has proved efficacious as a localizing tool in demonstrating the metabolic changes associated with temporal lobe epilepsy. To analyze the significance of these MR spectroscopy findings further, the authors explored the relationship between regional alterations in the NAA/Cr ratio in hippocampi measured preoperatively and histopathological findings in hippocampi resected in patients with intractable mesial temporal lobe epilepsy (MTLE). Methods. Twelve patients in whom the diagnosis of MTLE had been made and 12 healthy volunteers with no known history of neurological disease underwent high-resolution 1H MR spectroscopy imaging of NAA and Cr (0.64 cm3 nominal voxel resolution) in five voxels spanning the anteroposterior length of the hippocampus. The authors correlated the NAA/Cr ratio with neuropathological findings in resected hippocampi, specifically glial fibrillary acidic protein (GFAP) immunoreactivity and pyramidal neuronal loss. A linear regression analysis of the ipsilateral NAA/Cr ratio revealed a statistically significant relation to the extent of hippocampal neuronal loss in only the CA2 sector (correlation coefficient [r] = −0.66, p < 0.03). The ipsilateral NAA/Cr ratio displayed significant regressions with GFAP immunoreactivity from all the CA sectors (r values ranged from −0.69 and p < 0.01 for the CA4 sector to −0.88 and p < 0.001 for the CA2 sector) except for the CA1. The extent of neuronal cell loss in every hippocampal subfield (r = 0.71−0.74, p < 0.007), except the CA2 (p = 0.08), correlated to the extent of neuronal cell loss in the dentate gyrus. There was no significant relationship between the duration or frequency of seizures and the mean ipsilateral NAA/Cr ratio; however, the mean density of GFAP-immunopositive cells correlated with seizure frequency (p < 0.03). Conclusions. The NAA/Cr ratio may not measure the full extent of hippocampal neuronal cell loss. The significant association of the NAA/Cr ratio with the GFAP immunoreactivity of most CA sectors indicates that the NAA/Cr ratio may provide a more accurate measurement of recent neuronal injury caused by epileptic activity. The coupling between neuronal impairment and astroglial GFAP expression may indicate the close association between neuronal and glial dysfunction in patients with epilepsy.

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Vanderluit, Jacqueline L., Crystal A. Wylie, Kelly A. McClellan, Noel Ghanem, Andre Fortin, Steve Callaghan, Jason G. MacLaurin, David S. Park, and Ruth S. Slack. "The Retinoblastoma family member p107 regulates the rate of progenitor commitment to a neuronal fate." Journal of Cell Biology 178, no. 1 (June 25, 2007): 129–39. http://dx.doi.org/10.1083/jcb.200703176.

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The Retinoblastoma protein p107 regulates the neural precursor pool in both the developing and adult brain. As p107-deficient mice exhibit enhanced levels of Hes1, we questioned whether p107 regulates neural precursor self-renewal through the repression of Hes1. p107 represses transcription at the Hes1 promoter. Despite an expanded neural precursor population, p107-null mice exhibit a striking reduction in the number of cortical neurons. Hes1 deficiency rescues neurosphere numbers in p107-null embryos. We find that the loss of a single Hes1 allele in vivo restores the number of neural precursor cells at the ventricular zone. Neuronal birthdating analysis reveals a dramatic reduction in the rate of neurogenesis, demonstrating impairment in p107−/− progenitors to commit to a neuronal fate. The loss of a single Hes1 allele restores the number of newly generated neurons in p107-deficient brains. Together, we identify a novel function for p107 in promoting neural progenitor commitment to a neuronal fate.

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Pierce, Angela, Brian Bliesner, Mei Xu, Sheila Nielsen-Preiss, Greg Lemke, Stuart Tobet, and Margaret E. Wierman. "Axl and Tyro3 Modulate Female Reproduction by Influencing Gonadotropin-Releasing Hormone Neuron Survival and Migration." Molecular Endocrinology 22, no. 11 (November 1, 2008): 2481–95. http://dx.doi.org/10.1210/me.2008-0169.

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Abstract GnRH neurons must undergo a complex and precise pattern of neuronal migration to appropriately target their projections to the median eminence to trigger gonadotropin secretion and thereby control reproduction. Using NLT GnRH cells as a model of early GnRH neuronal development, we identified the potential importance of Axl and Tyro3, members of the TAM (Tyro3, Axl, and Mer) family of receptor tyrosine kinases in GnRH neuronal cell survival and migration. Silencing studies evaluated the role of Tyro3 and Axl in NLT GnRH neuronal cells and suggest that both play a role in Gas6 stimulation of GnRH neuronal survival and migration. Analysis of mice null for both Axl and Tyro3 showed normal onset of vaginal opening but delayed first estrus and persistently abnormal estrous cyclicity compared with wild-type controls. Analysis of GnRH neuronal numbers and positioning in the adult revealed a total loss of 24% of the neuronal network that was more striking (34%) when considered within specific anatomical compartments, with the largest deficit surrounding the organum vasculosum of the lamina terminalis. Analysis of GnRH neurons during embryogenesis identified a striking loss of immunoreactive cells within the context of the ventral forebrain compartment (36%) and not more rostrally. Studies using caspase 3 cleavage as a marker of apoptosis showed that Axl−/−, Tyro3−/− double-knockout mice had increased cell death in the nose and dorsal forebrain, supporting the underlying mechanism of cell loss. Together these data suggest that Axl and Tyro3 mediate the survival and appropriate targeting of GnRH neurons to the ventral forebrain, thereby contributing to normal reproductive function and cyclicity in the female.

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Shirvan, Anat, Michal Kimron, Vered Holdengreber, Ilan Ziv, Yehuda Ben-Shaul, Shlomo Melamed, Eldad Melamed, Ari Barzilai, and Arieh S. Solomon. "Anti-semaphorin 3A Antibodies Rescue Retinal Ganglion Cells from Cell Death following Optic Nerve Axotomy." Journal of Biological Chemistry 277, no. 51 (October 9, 2002): 49799–807. http://dx.doi.org/10.1074/jbc.m204793200.

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Damage to the optic nerve in mammals induces retrograde degeneration and apoptosis of the retinal ganglion cell (RGC) bodies. The mechanisms that mediate the response of the neuronal cells to the axonal injury are still unknown. We have previously shown that semaphorins, axon guidance molecules with repulsive cues, are capable of mediating apoptosis in cultured neuronal cells (Shirvan, A., Ziv, I., Fleminger, G., Shina, R., He, Z., Brudo, I., Melamed, E., and Brazilai, A. (1999)J. Neurochem.73, 961–971). In this study, we examined the involvement of semaphorins in anin vivoexperimental animal model of complete axotomy of the rat optic nerve. We demonstrate that a marked induction of type III semaphorin proteins takes place in ipsilateral retinas at early stages following axotomy, well before any morphological signs of RGC apoptosis can be detected. Time course analysis revealed that a peak of expression occurred after 2–3 days and then declined. A small conserved peptide derived from semaphorin 3A that was previously shown to induce neuronal death in culture was capable of inducing RGC loss upon its intravitreous injection into the rat eye. Moreover, we demonstrate a marked inhibition of RGC loss when axotomized eyes were co-treated by intravitreous injection of function-blocking antibodies against the semaphorin 3A-derived peptide. Marked neuronal protection from degeneration was also observed when the antibodies were applied 24 h post-injury. We therefore suggest that semaphorins are key proteins that modulate the cell fate of axotomized RGC. Neutralization of the semaphorin repulsive function may serve as a promising new approach for treatment of traumatic injury in the adult mammalian central nervous system or of ophthalmologic diseases such as glaucoma and ischemic optic neuropathy that induce apoptotic RGC death.

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Journal articles on the topic 'Neuronal cell loss'

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