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PubMed1991

Interphotoreceptor retinoid-binding protein (IRBP) in progressive rod-cone degeneration (prcd)--biochemical, immunocytochemical and immunologic studies.

Interphotoreceptor retinoid-binding protein (IRBP) is synthesized and secreted by photoreceptor cells and is thought to facilitate the transport of retinoids during the visual cycle as well as fatty acids essential to the maintenance of normal outer segment membranes. Proteins such as IRBP, which are unique to the photoreceptor cells in the retina, are prime candidates in the consideration of biochemical defects which could contribute to photoreceptor cell degeneration in man and animals. In this study, the association between IRBP and retinal degeneration was examined using the progressive rod-cone degeneration (prcd) mutant retina in dogs as an animal model. This study shows that loss of IRBP is not an early occurrence in prcd. IRBP is present in relatively normal amounts and distribution even at 1.7 years of age, a time when there is extensive visual cell disease and degeneration. By 2.7-3.0 years of age, IRBP loss correlates with the severity of the disease and concomitant loss of photoreceptor cells. IRBP immunoreactivity was present in the interphotoreceptor matrix (IPM) as long as inner segments were present to a significant degree. The late loss of IRBP immunoreactivity seems to be, therefore, the result of advanced degeneration and end-stage atrophy of the retina. In addition, immunological studies were carried out in order to examine the possible role of an autoimmune response against IRBP in the disease cascade. Normal, heterozygote and prcd-affected dogs had measurable antibody titers to IRBP, but there was no correlation between disease state and antibody levels.

Age Factors↗

PubMed1988

Morphometric and electrophysiological evidence for a diameter-based rate of degeneration in the optic nerve of the rat.

The diameter-based rate of degeneration in the rat's optic nerve was examined using coordinated morphological and electrophysiological techniques. Long-Evans, male rats were implanted with indwelling stimulating electrodes in the optic chiasm and recording electrodes in the stratum opticum of the superior colliculus. After 1 week, unilateral enucleation was performed with the unoperated side serving as the control. Electrically evoked recordings, obtained on the day of enucleation (D0), displayed three distinct peaks, Pre, N1 and P3, with peak latencies of 1.22, 2.22, and 4.04 ms, respectively. In a parallel set of rats, morphological analysis of the optic nerve over D1-7 was performed. Electron micrographs were taken of cross sections of the entire optic nerve from both the enucleated and unoperated (i.e., control) side. Computer-linked morphometric analysis of the ultrastructurally normal axons from each nerve was assembled in three-dimensional, diameter-based histograms at each time point. The control population consisted of axons with diameters ranging from less than 0.5-5.0 microns with a modal peak of 1.5 micron and a well developed tail in the 3.5-5.0 microns range. By D1,2, a selective loss of large diameter (greater than 3.5 microns) axons occurred in the optic nerve, with medium diameter (2.0-3.5 microns) axons degenerating at D4 and smaller diameter populations (less than 2.0 microns) persisting until later time points (D5-7). A linear regression analysis showed an exponential rate of degeneration which was a direct function of axonal diameter. In summary, this study demonstrates that the fiber population of the optic nerve is separable electrophysiologically and by its rate of degeneration, with larger diameter fibers degenerating faster in response to transection.

Analysis of Variance↗

PubMed1990

Idebenone attenuates neuronal degeneration induced by intrastriatal injection of excitotoxins.

Previous studies with the N18-RE-105 neuronal-like cell line and primary cortical cultures demonstrate that glutamate can produce a calcium-dependent, delayed form of neuronal degeneration that results from its competitive inhibition of cystine transport, which leads to cellular glutathione depletion and death by oxidative stress. Idebenone, a centrally active antioxidant used to treat multiinfarct dementia, protects cells from this form of glutamate-induced cytotoxicity in vitro. In the present study, we have examined the effects of systemic treatment with idebenone on the neurotoxic consequences of intrastriatal injection of kainic acid, quisqualic acid, or quinolinic acid, an NMDA receptor agonist, on neuronal degeneration. Striatal damage was assessed by quantitative neurochemistry with measurement of choline acetyltransferase activity and glutamate decarboxylase activity, by histochemical analysis for acetylcholinesterase and NADPH diaphorase staining and by behavioral assessment of circling produced by systemic apomorphine treatment 10 days after the unilateral lesion. The results indicate that treatment with idebenone provides significant protection against the neuronal degeneration induced by intrastriatal injection of kainic acid and quisqualic acid, but not the NMDA receptor agonist, quinolinic acid. The results suggest that oxidative stress may contribute to the proximate cause of neuronal degeneration induced by quisqualate and by kainate receptor agonists and that the mechanisms of neuronal degeneration caused by quisqualate/kainate receptor agonists differ from those associated with NMDA receptor agonists.

Animals↗

PubMed1995

Transganglionic degeneration in the gustatory system consequent to chorda tympani damage.

The chorda tympani taste nerve is prone to damage in humans. Chorda tympani damage results in taste loss accompanied by altered taste sensations, e.g., phantom tastes. To understand taste alterations this study explores the central and peripheral anatomical consequences of taste nerve injury in an animal model. The chorda tympani was severed in the middle ear of hamsters and the animals were allowed to survive for 2-161 days when sections of the brain were stained for degenerating axons with the Fink-Heimer method. Degenerating axons were present in the chorda tympani termination zone in the nucleus of the solitary tract of every case. Thus, peripheral nerve damage in the taste system results in degeneration of central axonal endings as in other sensory systems (e.g., trigeminal, vestibular). To evaluate whether the central degeneration results from ganglion cell death, geniculate ganglion cells were labeled with Fast blue by tongue injections before neurotomy, and the cells were counted 13-48 days after neurotomy. Numbers of labeled cells from experimental ganglia did not differ significantly from those in control ganglia. Moreover, the experimental cells could be double-labeled by tongue injections with a second marker, diamidino yellow or nuclear yellow, after 40 days postneurotomy. We conclude that degeneration of central axons after taste nerve section represents a long-lasting transganglionic process that likely disrupts the synaptology of the central taste system. The altered synaptology could relate to taste phenomena of central origin reported for nerve-injured patients. Geniculate ganglion cells generally survive neurotomy and can regenerate axons to the tongue.

Animals↗

PubMed1985

Axonal degeneration in large and small nerve fibres. An electron-microscopic and morphometric study.

Using computer-aided morphometric methods, axonal degeneration following nerve crush was analysed to reassess whether small fibres degenerate before large fibres or vice versa, or simultaneously. Axonal microtubule density was used as the criterion for determining the extent of fibre degeneration. Axonal areas and axonal microtubule numbers were recorded from a large sample of myelinated fibres in the right unoperated rat sural nerve and distal to crush in the left sural nerve. Both samples were divided into small and large fibre groups, according to axonal areas. Statistical analysis of the data confirmed a significant loss of microtubules from the left crushed nerve fibres but no significant difference in the relative loss of microtubules from small and large fibres. It is concluded, therefore, that in Wallerian degeneration, axonal breakdown, as assessed by microtubule loss, occurs simultaneously in small and large fibres. The findings are related to the electrophysiological changes which occur in Wallerian degeneration.

Animals↗

PubMedDate not supplied

Metabolic tapetoretinal degenerations.

There are a number of metabolic diseases which cause tapetoretinal degeneration, suggesting that pure pigmentary retinopathy may also be metabolic in nature. On the other hand tapetoretinal degenerations may have various modes of inheritance, so we may conclude that the metabolic disorder at the basis of these diseases is not unique and that tapetoretinal degenerations are heterogenic. In this article, some 450 published reports on tapetoretinal degenerations are reviewed. Based on these reports, the clinical and ocular manifestations, laboratory and histopathological findings, inheritance patterns, and treatments of various syndromes characterized by tapetoretinal degenerations are described. It is hoped that the gathering together of this information in one source will acid in the future understanding of metabolically based eye disease.

Adolescent↗

PubMed1995

Quantitative measurement of neuronal degeneration in organotypic hippocampal cultures after combined oxygen/glucose deprivation.

Organotypic hippocampal cultures were used to study cell degeneration during the recovery period after defined periods (30 and 60 min) of combined oxygen/glucose deprivation mimicking transient ischemic conditions. Staining with the fluorescent dye propidium iodide allowed detection of damaged cells. Fluorescence intensity was measured by an image analysis system and used to quantify cell damage at different time points during the recovery period (up to 22 h). At 30 min of oxygen/glucose deprivation cells in the CA1 area were relatively more sensitive compared to CA3 and dentate gyrus cells, with respect to the time course of degeneration and the percentage of affected cells. Expanding the oxygen/glucose deprivation period from 30 to 60 min drastically increased the percentage of cells dying in all hippocampal areas. Still, however, cells in CA1 degenerated faster compared to those in the CA3 area and dentate gyrus. A histological analysis of toluidine blue as well as MAP2-immunostained sections revealed that almost all neurons degenerated in all hippocampal areas following the 60-min deprivation period, whereas GFAP-stained astrocytes appeared to be unaffected. Therefore, neuronal degeneration could be quantified by taking the fluorescence intensity values 22 h after 60 min of oxygen/glucose deprivation as 100% neuronal damage. The possibility to quantify neuronal damage in organotypic cultures offers a useful tool for detailed studies on mechanisms of neuronal cell death in a cell culture system which is closer to in situ conditions than monolayer cell cultures.

Animals↗

PubMed1993

Microglial invasion and activation in response to naturally occurring neuronal degeneration in the ganglion cell layer of the postnatal cat retina.

Retinae of kittens between postnatal (P) days 2 and 10 were examined for the presence of degenerating neuronal profiles, normal nucleoli and microglia. Comparison of the numbers of degenerating profiles with numbers of axons lost from the optic nerve suggest that the majority of these profiles result from the degeneration of retinal ganglion cells. Analysis of local densities of the different profiles revealed different rates of cell loss, occurring at different times in central and peripheral retina. The period of rapid cell loss occurred between P2 and P3 in central retina compared to between P8 and P10 in peripheral retina. At both locations, these periods of rapid cell loss were accompanied by a decrease in the ratio of microglia to dying cells even though the absolute densities of microglia increased. However, calculation of the clearance times of cellular debris indicate that the speed of removal of degeneration products is greater during rapid cell loss, which suggests that cellular degeneration serves to activate the phagocytic process.

Animals↗

PubMed1992

Molecular and cellular mechanism of neuronal degeneration caused by nerve growth factor deprivation approached through PC12 cell culture.

1. Degenerative processes of PC12 cells after acute withdrawal of nerve growth factor (NGF) were characterized. PC12 cells treated with NGF share properties similar to sympathetic neurons, and only these cells responded to acute withdrawal of NGF by degeneration characterized by disappearance of growth cones, neurite disintegration, and eventually cell death. 2. The cell pool of ATP and release of lactate dehydrogenase (LDH) into medium were measured and taken as a quantitative measure of cell degeneration. 3. The release of LDH after NGF withdrawal was not completely blocked by cycloheximide or cordycepin, suggesting that active cell death occurred only partially in PC12 cells. Degeneration processes including neurite disintegration did not require protein synthesis. All the degenerative processes were completely prevented by chronic depolarization with high K+ and cyclic AMP. 4. Preliminary evidence was presented on a transient induction of the proto-oncogene c-fos upon acute withdrawal of NGF. Thus, one of the interesting aspects available from studies of PC12 cells would be to compare pathways initiated by NGF deprivation to those activated by NGF exposure to naive PC12 cells, since the latter pathways have been extensively studied. 5. These results suggest that PC12 cells serve as a model system for studying neuronal degeneration caused by acute withdrawal of NGF. We also suggest that NGF removal elicits divergent cellular signalling pathways leading to cell degeneration, some of which may be utilized in common with those activated by NGF exposure to naive PC12 cells.

Adenosine Triphosphate↗

PubMed1982

Delay by drugs of adrenergic nerve degeneration after proximal or distal sympathectomy of the submaxillary gland.

1. Degeneration of nerve terminals of the submaxillary gland of the rat proceeds at a faster rate after crushing adrenergic nerves close to the gland than after ganglionectomy. 2. Bretylium, pargyline, nialamide and clorgyline delayed degeneration to the same extent after either type of denervation. 3. Chlorpromazine and pentobarbitone also delayed adrenergic degeneration, effect related to the hypothermia induced by these drugs. 4. Colchicine applied on the nerve trunk innervating the right gland delayed not only degeneration of the ipsilateral nerve terminals but the contralateral gland as well. 5. From the data obtained it seems probable that the drugs tested delay adrenergic nerve degeneration at the levels of nerve terminals. This effect is not related to lysosomal stabilization.

Acid Phosphatase↗

PubMed1988

Trimethyltin-induced neuronal damage in the rat brain: comparative studies using silver degeneration stains, immunocytochemistry and immunoassay for neuronotypic and gliotypic proteins.

Trimethyltin is a neurotoxicant which produces a distinct pattern of neuronal cell death following peripheral administration of a single dose (8 mg/kg, i.p.) in rats. The cupric-silver degeneration stain was used to produce an atlas documenting the distribution and time course of trimethyltin-induced neuronal damage in adult, male Long-Evans rats. Animals were examined at survival times of 1, 2, 3, 4, 5, 7, 10 and 18 days after intoxication. The earliest degeneration was observed at day 1 in the intermediate and ventral divisions of the lateral septal nucleus, followed by development of degeneration on days 2-4 in neuron populations including the septohippocampal nucleus, septohypothalamic nucleus, anterior olfactory nucleus, bed nucleus of the stria terminalis, endopiriform nucleus, parafascicular nucleus, superior colliculus, interstitial nucleus of the posterior commissure, inferior colliculus, pontine nuclei, raphe nuclei, pars caudalis of the spinal trigeminal nucleus, the caudal aspect of nucleus tractus solitarius, dorsal vagal motor nucleus, granule cells in the dentate gyrus, pyramidal cells in CA fields of the hippocampus, and of neurons in the subiculum, pyriform cortex, entorhinal cortex and neocortex (mainly layer Vb and VI). This was followed by degenerative changes on days 5-7 in other structures, including the amygdaloid nuclei, the ventral posterolateral and ventral posteromedial thalamic nuclei and the periaqueductal gray. The distribution of terminal degeneration from these neurons indicate that specific pools of cells are affected in each structure, and the time course suggests somatofugal degeneration. The trimethyltin damage was also assessed with immunocytochemical visualization of a neuronotypic protein, protein-O-carboxyl methyltransferase and a radioimmunoassay for glial fibrillary acidic protein. Protein-O-carboxyl methyltransferase immunoreactivity was altered in neuronal populations damaged by trimethyltin, but did not appear to be either as sensitive or selective an assay of neuronal damage as the silver stain, especially at short survival times. Glial fibrillary acidic proteins were dramatically elevated 21 days after trimethyltin intoxication, particularly in areas of extensive damage. These studies revealed advantages and problems encountered in the use of each technique in assessing neurotoxic effects, forming a basis for discussion of the relative merits of using a battery of specific molecular probes for neurotoxicity evaluations.

Animals↗

PubMedDate not supplied

Use of an amino-cupric-silver technique for the detection of early and semiacute neuronal degeneration caused by neurotoxicants, hypoxia, and physical trauma.

A new amino-cupric silver protocol is described for detection of neuronal degeneration. We describe its selectivity in visualizing both early and semiacute degeneration after intracerebral or systemic administration of a variety of neurotoxicants in rats, and after transient ischemic episodes in gerbils. As early as 5 min after physical trauma, or 15 min following either intrastriatal injections of glutamate analogs or exposure to ischemic episodes, neuronal silver staining was evident at primary sites of trauma (i.g. injection sites) and at hodologically related secondary sites. With intoxication by peripheral injections of trimethyltin (IP) or intracerebral injections of Doxorubicin, reproducible patterns of degeneration are demonstrable after 24 h or after 9-13 days, respectively. The amino-cupric silver method permits simultaneous detection of all neuronal compartments against a clear background. Degeneration in the neuronal cell bodies, dendrites, axons and terminals, as well as the recruitment of new structures in a progressive pathologic process, could be accurately followed. The inclusion of new reagents increased the sensitivity vis-à-vis previous versions of the cupric-silver method. The advantages and disadvantages of the current method in comparison with other means of neurotoxic assessment are discussed in detail, with special emphasis on its unique ability to discriminate irreversible degenerative phenomena and degeneration of axonal components in cases where the cell body remains apparently intact. The amino-cupric silver method is an especially useful tool for surveying neuronal damage in basic neuroscience investigations and in neuropathologic and neurotoxic assessment.

Animals↗

PubMed2005

Regulatory aspects of drug approval for macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries with approximately 15 million people with the disease in the United States. AMD is characterized as a progressive degenerative disease of the macula. There are two forms of AMD: neovascular and non-neovascular. The non-neovascular form of AMD is more common and leads to a slow deterioration of the macula with a gradual loss of vision over a period of years. The neovascular form of the disease is responsible for the majority of cases of severe vision loss and is due to proliferation of abnormal blood vessels behind the retina. These blood vessels leak blood and fluid into the retina, which results in visual abnormalities. The development of these abnormal blood vessels is due in part to the activity of VEGF (vascular endothelial growth factor) and its inhibition is expected to impact on the onset and/or severity of vision loss associated with the proliferation of abnormal blood vessels. Age-related macular degeneration is an underserved treatment population. Visudyne (verteporfin for injection), Novartis Ophthalmics, is FDA approved for the treatment of patients with predominantly classic subfoveal choroidal neovascularization due to age-related macular degeneration, pathologic myopia or presumed ocular histoplasmosis. Pegaptanib sodium (Macugen, Eyetech Pharmaceuticals, Inc. and Pfizer, Inc.) is indicated for the treatment of neovascular (wet) age-related macular degeneration. This article will review the approval pathway for these two products and that required of future products indicated for macular degeneration.

Aptamers, Nucleotide↗

PubMed2004

Adenoviral-mediated gene transfer to retinal explants during development and degeneration.

Naturally occurring mutations of the beta subunit of the cyclic guanosine monophosphate (cGMP) phosphodiesterase (beta-PDE) gene in rod photoreceptors of mice and dogs are similar to one of the inherited retinal degenerations termed retinitis pigmentosa in humans. Defects in the rod beta-PDE gene leading to photoreceptor cell degeneration in retinal degenerative (rd) mice can be corrected by transfer of a wild type beta-PDE gene. However, the rapid photoreceptor degeneration in this mutant makes the study of gene therapy difficult. Since the retinal degeneration is slowed in vitro, we have employed retinal explants from rd mice to study factors influencing viral transduction. Retinal explants provide a rapid, efficient method to compare the transduction efficiency of adenoviral vector-mediated reporter gene delivery at different ages in normal and rd mice. Retinal explants from postnatal day (P)2 to P28 control (C57BL/6J) and P2-P42 rd mice were exposed for 20 hr to 2.5 x 10(8) plaque forming units (pfu) ml(-1) of adenoviral vector with a beta-galactosidase (Lac Z) reporter gene (Ad-CMV-Lac Z). After incubation in vector-free media for an additional 3 days, the explants were fixed and histochemically stained for beta-galactosidase to reveal Lac Z gene expression. The explants were also embedded and sectioned for light microscopic observation. Transduction efficiency was higher in rd mice than in controls on all postnatal days examined. In normal retinal explants, expression of the Lac Z gene increased from P2 to a peak around P7-P8, then decreased at subsequent ages; little transduction could be found after P17. In rd mice transduction efficiency of Ad-CMV-Lac Z increased from P2 to P7, decreased by P10 and increased again after P10. The most dramatic increase in the transduction efficiency occurred in the rd retina between P10 and P15 when Lac Z was intensely expressed throughout the retina. Microscopic examination of retinal sections revealed the types and distribution of Lac Z-positive cells responsible for the deep blue staining in the retinal whole mount. In normal and rd mice, Lac Z-positive cells were located throughout the retina. However, larger numbers of Lac Z-positive cells were present at all ages examined in retinal explants from rd mice compared to normal mice. These data indicate a difference in transduction efficiency between normal and rd mice, especially after P12, and suggest efficient adenovirus-mediated gene transfer is more attainable in developing or degenerating retina. Thus, transduction efficiency in rd mice depends on the relationship between development, maturation and the degenerative state of the photoreceptor cells.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2006

Degeneration and proliferation of astrocytes in the mouse dentate gyrus after pilocarpine-induced status epilepticus.

Astrocytes are relatively resistant to injury compared to neurons and oligodendrocytes. Here, we report transient region-specific loss of astrocytes in mice early after pilocarpine-induced status epilepticus (SE). In the dentate hilus, immunoreactivity for glial acidic fibrillary protein (GFAP) was decreased, and the number of healthy appearing GFAP- or S100beta-positive cells was significantly reduced (> or =65%) 1 and 3 days after pilocarpine-induced SE. Many remaining GFAP-positive cells were shrunken, and 1 day after SE electron microscopy revealed numerous electron-dense degenerating astrocyte processes and degenerating glial somata in the hilus. Degeneration of GFAP-expressing cells may be linked to hilar neuronal death, because we did not observe loss of astrocytes after kainate-induced SE, after which hilar neurons remained intact. Ten days after SE, hilar GFAP immunoreactivity had returned, partially from GFAP-positive cells in the hilus. Unlike control mice, many GFAP-positive hilar processes originated from cell bodies located in the subgranular zone (SGZ). To investigate whether proliferation contributes to hilar repopulation, we injected 5-bromo-2'-deoxyuridine (BrdU) 3 days after SE. Five hours later and up to 31 days after SE, many BrdU/GFAP colabeled cells were found in the hilus and the SGZ, some with hilar processes, indicating that proliferation in both areas contributes to generation of hilar astrocytes and astrocyte processes. In contrast to pilocarpine-induced SE in mice, astrocyte degeneration was not found after pilocarpine-induced SE in rats. These findings demonstrate astrocyte degeneration in the mouse dentate hilus specifically in the mouse pilocarpine epilepsy model, followed by astrogenesis leading to hilar repopulation.

Animals↗

PubMed2006

Autoantibodies to p75/LEDGF, a cell survival factor, found in patients with atypical retinal degeneration.

We have identified a group of patients with an atypical retinal degeneration having anti-retinal autoantibodies in their sera. This select population is characterized by a progressively severe loss of vision associated with a decrease in photoreceptor function, abnormal pigmentation of the retinal pigment epithelium and a negative family history of retinal dystrophy. Immunohistochemical analysis on mouse retinal tissues with sera from this group of patients demonstrated high titers of anti-retinal antibodies (320 to 1,280). Anti-retinal reactivity at these levels was not detected in sera from normal individuals, or from patients with uveitis or known genetic retinal degenerations. One antigen that was identified from a retina cDNA library with sera from a patient with atypical retinal degeneration was lens epithelium-derived growth factor (LEDGF). Western blot analysis revealed that sera from all three patients demonstrated reactivity to p75/LEDGF, a survival factor that protects cells from oxidative, thermal and UV damage. In conclusion, we have found a novel group of patients with a retinal degeneration of non-paraneoplastic, non-familial origin demonstrating immunoreactivity to an autoantigen, p75/LEDGF, heretofore not associated with this disease. Finally, identification of specific anti-retinal antibodies may have applications in the diagnosis and management of retinal degeneration.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Sodium-mediated axonal degeneration in inflammatory demyelinating disease.

Axonal degeneration is a major cause of permanent neurological deficit in multiple sclerosis (MS). The mechanisms responsible for the degeneration remain unclear, but evidence suggests that a failure to maintain axonal sodium ion homeostasis may be a key step that underlies at least some of the degeneration. Sodium ions can accumulate within axons due to a series of events, including impulse activity and exposure to inflammatory factors such as nitric oxide. Recent findings have demonstrated that partial blockade of sodium channels can protect axons from nitric oxide-mediated degeneration in vitro, and from the effects of neuroinflammatory disease in vivo. This review describes some of the reasons why sodium ions might be expected to accumulate within axons in MS, and recent observations suggesting that it is possible to protect axons from degeneration in neuroinflammatory disease by partial sodium channel blockade.

Animals↗

PubMed2005

Regulation of Wallerian degeneration and nerve growth factor withdrawal-induced pruning of axons of sympathetic neurons by the proteasome and the MEK/Erk pathway.

Treatment of transected distal axons of rat sympathetic neurons in compartmented cultures with MG132 (5 microM) and other inhibitors of proteasome activity, preserved axonal mitochondrial function, assessed by Mitotracker-Orange and MTT staining, for at least 24 h. MG132 similarly protected axons from undergoing branch elimination (pruning) in response to local NGF deprivation. Axons protected by MG132 displayed persistent phosphorylation of Erk1/2, and pharmacological inhibition of MEK activity with U0126 (50 microM) restored rapid axonal degeneration. Therefore, the proteasome does not appear to be necessary as a general effector of protein degradation during axonal degeneration. Rather, the proteasome functions in the regulation of signaling pathways that control axonal survival and degeneration. Specifically, the down-regulation of the MEK/Erk pathway by the proteasome plays roles in Wallerian degeneration of severed axons and axonal pruning in response to local NGF deprivation. Identification of the pathways that regulate axonal survival and degeneration will provide possible target sites for pharmacological treatments of neurodegenerative diseases and traumatic injury.

Animals↗