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PubMed2007

Motor neuron degeneration in amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice: mechanisms of mitochondriopathy and cell death.

The mechanisms of human mutant superoxide dismutase-1 (mSOD1) toxicity to motor neurons (MNs) are unresolved. We show that MNs in G93A-mSOD1 transgenic mice undergo slow degeneration lacking similarity to apoptosis structurally and biochemically. It is characterized by somal and mitochondrial swelling and formation of DNA single-strand breaks prior to double-strand breaks occurring in nuclear and mitochondrial DNA. p53 and p73 are activated in degenerating MNs, but without nuclear import. The MN death is independent of activation of caspases-1, -3, and -8 or apoptosis-inducing factor within MNs, with a blockade of apoptosis possibly mediated by Aven up-regulation. MN swelling is associated with compromised Na,K-ATPase activity and aggregation. mSOD1 mouse MNs accumulate mitochondria from the axon terminals and generate higher levels of superoxide, nitric oxide, and peroxynitrite than MNs in control mice. Nitrated and aggregated cytochrome c oxidase subunit-I and alpha-synuclein as well as nitrated SOD2 accumulate in mSOD1 mouse spinal cord. Mitochondria in mSOD1 mouse MNs accumulate NADPH diaphorase and inducible nitric oxide synthase (iNOS)-like immunoreactivity, and iNOS gene deletion extends significantly the life span of G93A-mSOD1 mice. Prior to MN loss, spinal interneurons degenerate. These results identify novel mechanisms for mitochondriopathy and MN degeneration in amyotrophic lateral sclerosis (ALS) mice involving blockade of apoptosis, accumulation of MN mitochondria with enhanced toxic potential from distal terminals, NOS localization in MN mitochondria and peroxynitrite damage, and early degeneration of alpha-synuclein(+) interneurons. The data support roles for oxidative stress, protein nitration and aggregation, and excitotoxicity as participants in the process of MN degeneration caused by mSOD1.

Age Factors↗

PubMed1980

Development and degeneration of retina in rds mutant mice: light microscopy.

Changes during the development and degeneration of the retina in 020/A mice, which are homozygous for the newly reported rds (retinal degeneration slow), gene were studied by histological and enzyme-histochemical methods with Balb/c mice carrying the normal allele as control. During normal development the total thickness of the retina grows from the time of birth till the age of 21 days and thereafter gradually diminishes, while the thicknesses of the component layers show a characteristic and differential change in course of their histogenesis. In the normal retina the perikarya of the cones are more frequent in the central than in the peripheral areas. The cone frequency in the central retina, but not in the periphery, increases with age and implies selective loss of rod cells in older animals. In the homozygous rds mice, the receptor layer remains rudimentary, but the other retinal layers show a normal trend of growth during the first 2 weeks after birth. Thereafter th morphological layers containing visual cell structures--the receptor, the outer nuclear, and the outer plexiform layers--begin to reduce. The loss of visual cells is readily marked by the reduction of the outer nuclear layer and is first evident at 2 weeks after birth. Degeneration is more rapid up to the age of 2-3 months, when the outer nuclear layer is reduced to half of its original thickness; thereafter degeneration progresses more slowly. The receptor and the outer plexiform layers are also simultaneously reduced. At 9 months, the peripheral parts of the retina, and at 12 months, the entire retina is completely lacking in visual cells. In the central retina of the mutant, rod and cone cell populations are equally affected up to the age of 6 months, as their relative frequency remains similar to the normal. In the peripheral retina, where cell loss is more pronounced, and in the central retina at 9 months an increase in relative frequency of cones is recorded and indicate increased susceptibility of the rods to later degenerative changes. The inner parts of the retina, including inner nuclear, inner plexiform, and ganglion cell layers, remain morphologically unaffected until irregular vascularization follows total loss of visual cells. The pigment epithelium is also affected at this late stage and appears depleted and patchy. In the normal retina, macrophages which are positively stained for the enzyme N-acetyl-beta-glucosaminidase appear in the inner layers with the growth of the retinal vasculature. In the mutant, increased frequency and stainability of the macrophages are discernible in the inner retina at 11 days. The macrophages migrate outwards and are observed in the outer nuclear layer and in the optic ventricle during the period of degeneration. These findings are compared with the observations in the other retinal degeneration mutants in rodents, and in retinitis pigmentosa in humans. The suitability of the rds mice as an animal model system for the human disease is emphasized.

Animals↗

PubMed1982

Retinal degeneration in the pcd cerebellar mutant mouse. II. Electron microscopic analysis.

The cerebellar ataxia in Purkinje cell degeneration (pcd) mutant mice results from the rapid loss of Purkinje cells between 3 and 5 weeks after birth. The loss of photoreceptors in these mutants begins about the same time but proceeds slowly, with most photoreceptors being lost by 1 year of age. In this study the retinas of pcd/pcd mice and their littermate controls from the age of 10 postnatal days to 15 months were analyzed by electron microscopy. The first signs of photoreceptor cell degeneration are apparent in the region of photoreceptor inner segments as early as postnatal day 13, and more prominently at day 18. During this time, the degeneration is characterized by a large number of vesicles, ranging in diameter from 150 to 350 nm, which are located in the extracellular space adjacent to the photoreceptor inner segments. Analysis of serial sections shows that most of these membrane-bound degeneration profiles are tubular in shape and some are continuous with the cell membrane of the inner segment. Therefore, these "profiles" are thought to arise from tubular outpocketings of the inner segments which cleave off to form isolated membrane-bound profiles. This represents a new and unusual form of photoreceptor degeneration. While the most obvious abnormality in the retina is degeneration of photoreceptor cells, Müller cells also appear to be affected, with swollen apical processes often seen coursing through the outer nuclear layer.

Animals↗

PubMed1984

Time course of mossy fiber degeneration following pontine ablation in the rat.

The normal ultrastructure of mossy fiber terminals within the ansiform lobule of the rat was investigated in parasagittal sections of the cerebellar cortex. Four types of mossy fiber varicosities (simple and complex dispersed, simple and complex clustered) were distinguished on the basis of the presence or absence of clublike excrescences and the concentration of synaptic vesicles within the cortical zone of the terminal. Removal of the pontocerebellar input to the contralateral cerebellar hemisphere was performed electrolytically. Such lesions, when placed in the basilar pontine gray using a dorsal approach, resulted in the degeneration of nearly the entire population of mossy fiber varicosities within the contralateral ansiform lobule. As early as 3 days following pontine ablation, degenerative changes were observed within the synaptic portions of the mossy fibers. Two distinct axonal reactions were apparent within this population of degenerating varicosities. A small population of mossy fiber varicosities (12%) of the simple clustered variety underwent a rapid course of electron-dense degeneration, which was complete by the fifth day. These mossy fiber varicosities were very susceptible to phagocytosis by reactive glial elements. The second group which consisted of simple (60%) and complex (26%) varieties of dispersed terminals, underwent a very slow course of electron-dense degeneration. Reactive glial cells were rarely found in association with this second group of degenerating varicosities. As a result, most glomeruli were found to contain debris from degenerating mossy fiber varicosities throughout the first 57 days following pontine lesions. The majority of the cerebellar glomeruli, however, were denervated by 80 days.

Afferent Pathways↗

PubMed1986

Transganglionic degeneration in vibrissae innervating primary sensory neurons of the rat: a light and electron microscopic study.

Previous studies have shown that transection of peripheral branches of primary sensory neurons leads to light microscopical degeneration argyrophilia and ultrastructural changes in the central termination areas of these neurons. This type of degeneration has been termed transganglionic degeneration (TGD). In the present experiments TGD has been studied specifically in neurons innervating the rat vibrissae at the light and electron microscopic levels. Light microscopically, small amounts of degeneration argyrophilia are observed in the magnocellular zone of the trigeminal subnucleus caudalis at 8-14 days survival. At longer survival times there are substantial amounts of degeneration in this area. At the ultrastructural level the first signs of TGD are observed at 6 days survival, when some terminals show a small increase in electron density, loss of synaptic vesicles, and mitochondrial disintegration. Terminals showing a more advanced increase in electron density become common at 8 days survival, but few of them are still left at 14 days survival. Neurofilamentous terminals appear in small numbers 8-14 days postoperatively. Various forms of degeneration in myelinated axons are observed from 8 days survival and are common also at 80 days survival. Electron-dense axons are rather unfrequent, but more or less disrupted myelin sheaths containing disintegrated axoplasmic remnants and empty areas are common as well as extremely expanded myelin sheaths. Glial cells containing axonal and myelin debris are seen from 8 days survival and become a more common finding at longer survivals. A most striking finding 8-10 days postoperatively is a complex relationship between glial cells and less darkened terminals, indicating phagocytosis before reaching an entirely darkened state. The findings clearly show that peripheral nerve transection leads to severe central alterations in a population of mechanoreceptor neurons innervating the vibrissae of the adult rat.

Animals↗

PubMed1990

Capsaicin-induced neuronal degeneration in the brain and retina of preweanling rats.

Capsaicin is a neurotoxin known for its ability to cause degeneration of small unmyelinated primary sensory neurons in both spinal and cranial nerves. Although lower motor neurons do not degenerate following capsaicin treatment, the extent to which capsaicin may damage neurons in the brain has not been thoroughly evaluated. This study examines the effects of systemic capsaicin (50-150 mg/kg) on the central nervous system of 10-day-old rats. Rat pups were injected with capsaicin or the injection vehicle and sacrificed 6 hours-10 days later. Brains, spinal cords, and retinas were stained with cupric silver to label degenerating neurons. As previously reported for capsaicin-treated rats, degenerating nerve terminals were present in areas receiving primary afferent input: the spinal cord dorsal horn, spinal trigeminal nucleus, nucleus of the solitary tract, and area postrema. However, degenerating terminals were also present in areas not known to receive primary sensory innervation: the inferior olivary nucleus, sphenoid nucleus, medial and olivary pretectal nuclei, interpeduncular nucleus, interfascicular nucleus, caudal linear, dorsal, median, and paramedian raphe nuclei, supramammillary area, lateral habenula, ventrolateral geniculate nucleus, ventral reuniens nucleus, ventromedial hypothalamic nucleus, lateral hypothalamic and preoptic areas, suprachiasmatic nucleus, septohypothalamic nucleus, bed nucleus of the stria terminalis, lateral septal nucleus, accumbens shell, olfactory bulb, and retina. Some areas where capsaicin caused degeneration in rat pups do not appear to be capsaicin-sensitive in adult rats. Results indicate that (1) capsaicin's neurotoxicity is not limited to primary sensory neurons and (2) developmental factors may alter the capsaicin sensitivity of some neuronal projections within the brain.

Animals↗

PubMed1991

Prior optic nerve transection reduces capsaicin-induced degeneration in rat subcortical visual structures.

Capsaicin is a neurotoxin capable of causing degeneration in specific sites throughout the neuraxis, including the suprachiasmatic nucleus (SCh), the ventrolateral geniculate nucleus (VLG), the intergeniculate leaflet (IGL), and the olivary and medial pretectal nuclei (OPT and MPT). In this experiment, we tested the hypothesis that capsaicin-induced terminal degeneration in the SCh, VLG, IGL, OPT, and MPT results from destruction of retinal ganglion cells and their axonal projections to these sites. In the first experiment, silver stains were used to examine degeneration in the retina induced by systemic capsaicin treatment. Capsaicin caused degeneration of ganglion cells, bipolar cells, and nerve terminals in the retina, which could be observed between 2 and 24 hours after treatment. In the second experiment, 15-day-old rat pups were enucleated unilaterally. Five days or 2, 5, or 10 months later, they were injected systemically with capsaicin and killed 6 hours (pups) or 18 hours (adults) later for analysis with a cupric silver stain. In rats of all ages, prior monocular enucleation reduced or eliminated capsaicin-induced degeneration in the contralateral SCh, VLG, IGL, OPT, and MPT. In the third experiment, rat pups were treated systemically with capsaicin or vehicle solution at 12 days of age and given unilateral intravitreal injections of cholera toxin conjugated to horseradish peroxidase (CT-HRP) 3 days prior to sacrifice at 20 days of age. Transport of CT-HRP to the SCh, VLG, IGL, MPT, and OPT was attenuated but not abolished by capsaicin pretreatment. Results suggest that capsaicin causes degeneration in the SCh, VLG, IGL, MPT, and OPT by selective destruction of a subpopulation of retinal ganglion cells with axonal projections to these sites.

Animals↗

PubMed1993

Adrenalectomy-induced granule cell degeneration in the rat hippocampal dentate gyrus: characterization of an in vivo model of controlled neuronal death.

The recent discovery that adrenalectomy results in hippocampal granule cell loss suggested that this phenomenon might be useful as a model of selective, experimentally controlled neuronal death possibly relevant to neurodegenerative disorders. This study was designed to provide a detailed qualitative anatomical description of the phenomenon and to determine whether adrenalectomy-induced dentate granule cell degeneration constitutes a reliable model of selective neuronal death. Silver impregnation staining revealed that granule cell degeneration begins immediately after adrenalectomy and continues for months in both sexes, in young and older adults, and in all strains tested. In one group of 77 adrenalectomized rats, 82% exhibited silver-impregnated granule cells. This phenomenon is extraordinarily selective in that no neurons other than dentate granule cells degenerated after adrenalectomy. There was considerable variability among animals in the number of cells degenerating at a given time-point or in the degree of ultimate cell loss. In the most extreme cases, virtually complete granule cell loss was present throughout approximately 80% of the dentate gyrus. Nissl staining revealed that degenerating granule cells exhibited coalescing of nuclear chromatin into multiple nuclear bodies and pyknosis without accompanying glial swelling. This morphology is distinct from the necrosis caused by other neurotoxic insults and is the subject of the ultrastructural companion paper identifying this type of cell death as apoptosis. Taken together, these results indicate that adrenalectomy reliably initiates an immediate, highly selective, and long-continuing process of hippocampal granule cell degeneration that exhibits morphological features characteristic of apoptosis, rather than necrosis. The possibility that this apoptotic cell death involves a biochemical cascade relevant to programmed cell death and/or neurodegenerative diseases suggests that this model may be valuable for studies of neuronal death and its prevention. Some practical guidelines for use of this model are described.

Adrenalectomy↗

PubMed1993

Retinal degeneration in the nervous mutant mouse. II. Electron microscopic analysis.

Nervous mutant mice (nr/nr) show a rapid loss of most of cerebellar Purkinje cells between the ages of 3 and 7 weeks, as well as a progressive photoreceptor cell degeneration that occurs most rapidly between postnatal days (P) 13 and 19, but with a much slower attrition during the subsequent months. We have carried out an electron microscopic analysis of nr/nr and littermate control mice at representative ages to characterize the subcellular cytopathological changes in this form of retinal degeneration, to gain insight into photoreceptor cell degeneration mechanisms by comparing these changes to those in other rodent forms of retinal degeneration, and to compare the photoreceptor changes with those of cerebellar Purkinje cells. Ultrastructural observations were limited to rod photoreceptors, since the number of cones was limited in our micrographs. The retinas of nr/nr mutant mice can be distinguished from those of normal littermates as early as postnatal day (P) 6. At this time, some of the mitochondria in rod inner segments are larger and more rounded than normal. This represents the earliest cytopathological change thus far observed in this mutant. As early as P9 and thereafter, the volume and integrity of rod outer segment membranes are reduced from normal. In the inner segments of some rod photoreceptor cells, there is a reduction in the volume or number of polyribosomes as early as P11, a reduction in rough endoplasmic reticulum as early as P13, and reduced incidence and less organized Golgi membranes as early as P16. Qualitative evaluation and quantitative stereological analysis show that the enlarged mitochondria in rod inner segments never become normal in shape or size. No changes are seen in the inner retinal layers at any age. Despite similarities with inherited retinal dystrophy in the Royal College of Surgeons rat, as noted in the original description of retinal degeneration in nr/nr mice, ultrastructural features clearly distinguish these mutants. Moreover, nr/nr mice can be distinguished from all other murine forms of retinal degeneration by electron microscopy.

Animals↗

PubMed1993

Growth and degeneration of axons on astrocyte surfaces: effects on extracellular matrix and on later axonal growth.

Cultured astrocytes deposit an extracellular matrix which has been shown by immunocytochemistry to react with antibodies to tenascin, laminin, and fibronectin. Neuronal-glial interaction down-regulates these components of the matrix, causing a reduction in extracellular matrix localized to areas of contact with axons. Axons used for these experiments were from embryonic rat retinal explants. In some experiments explants were removed from the co-cultures and their axons allowed to degenerate. Degeneration of axons did not reverse the local reduction of extracellular matrix brought about by axon outgrowth. The period of axon outgrowth studied was 4-5 days; the period of degeneration was 2-3 days. Astrocytes alone, astrocytes with intact retinal explants, and astrocytes with 2-day degenerated retinal axons were tested for their ability to support neurite outgrowth from embryonic rat cortical neurons. Neurite outgrowth occurred on all astrocyte cultures. Cortical neurite lengths, measured 2 days after plating, were not significantly different between astrocytes alone and astrocytes with degenerated retinal axons. However, there was a tendency for neurites to be shorter on astrocytes with intact retinal axons present. Two conclusions may be drawn from these results. First, the state of differentiation of astrocytes, as marked by their assembly of extracellular matrix, is altered by contact with axons. Second, degeneration of axons alone, in the absence of other cell types, is not a sufficient signal to reestablish assembly of extracellular matrix. However, neither is it a sufficient signal to render astrocytes inhospitable to further axonal outgrowth or regeneration.

Animals↗

PubMed1988

Ultrastructural and paraphenylene studies of degeneration in the primate visual system: degenerative remnants persist for much longer than expected.

It is a widely held belief that the products of axonal degeneration in the CNS are transitory and are caused by metabolic and phagocytic processes. However, recent light microscopic examinations of human and primate brains using the paraphenylene diamine staining method (PPD), which stains degenerating axons, have confirmed that the products of degeneration persist for years in visual pathways. The routine utilization of the PPD method for delineating human visual pathways requires further confirmation of axonal degeneration. Optic nerves, optic tracts, and lateral geniculate nuclei were collected from human brains that had clinical documentation of optic nerve damage prior to death. Optic nerves, optic tracts, and lateral geniculate nuclei taken from the brains of cynomolgus monkeys that had undergone enucleation 3 months to 1 year prior to sacrifice were also examined. All tissue was processed for electron microscopy; ultrathin sections were cut for electron microscopy, and consecutive sections were cut for light microscopy. In all cases, the homology of the degenerated processes was confirmed between the light microscopic (PPD) and the electron microscopic sections. Such ultrastructural examination demonstrates that the products of axonal degeneration remain in the primate visual system longer than previously supposed.

Animals↗

PubMed1994

Delayed macrophage responses and myelin clearance during Wallerian degeneration in the central nervous system: the dorsal radiculotomy model.

All aspects of Wallerian degeneration (WD)--axonal breakdown, glial and macrophage responses, and clearance of myelin debris--have generally been considered to occur more slowly in the central nervous system (CNS) than in the peripheral nervous system (PNS). We reevaluated this issue by comparing the temporal pattern of Wallerian degeneration in nerve fibers with segments extending through both the PNS and the CNS. The L4, L5, and L6 dorsal roots in the rat were transected, and WD in the dorsal roots and the dorsal columns was compared at intervals up to 8 months, using electron microscopy and immunostaining to identify and characterize the different cell types. The initial breakdown of axoplasm was complete by 72 h both in the PNS and in the CNS portions of these axons. All other aspects of WD were strikingly delayed in the CNS when compared to those in the PNS. Macrophages (from the circulation) increased in number (Days 2-4 after axotomy) in the root. In contrast, although there was an early and transient period (peaking at Day 3) of microglial activation in the degenerating dorsal column, the appearance of round macrophages was delayed until Days 18-21. Both axonal debris and myelin debris were almost completely cleared by 30 days in the PNS, but remained over 90 days in the CNS. Axonal regeneration was vigorous in the dorsal root but these sprouts did not invade the dorsal columns. The dorsal root entry zone provided a sharp anatomic demarcation between the PNS and CNS patterns of Wallerian degeneration. These results suggest that circulating macrophages have ready access to degenerating peripheral nerves, but are largely or completely excluded from degenerating CNS tracts, so that the macrophages (that ultimately appear) originate primarily from the stellate microglia.

Animals↗

PubMed1998

Degeneration of spared axons following partial white matter lesion: implications for optic nerve neuropathies.

Neuroprotective therapy is a relatively new development in the approach to the treatment of acute and chronic brain damage. Though initially viewed in the framework of acute CNS injuries, the concept was recently extended to include chronic injuries, in which at any given time there are some neurons in an acute phase of degeneration coexisting with others that are healthy, marginally damaged, or dead. The healthy neurons and those that are only marginally damaged are the potential targets for neuroprotection. For the development of neuroprotective therapies, it is essential to employ an animal model in which the damage resulting from secondary degeneration can be quantitatively distinguished from primary degeneration. This is of particular relevance when the site of the damage is in the white matter (nerve fibers) rather than in the gray matter (cell bodies). In the present work we reexamine the concepts of secondary degeneration and neuroprotection in white matter lesions. Using a partial crush injury of the adult rat optic nerve as a model, we were able to assess both primary and secondary nerve damage. We show that neurons whose axons were not damaged or only marginally damaged after an acute insult will eventually degenerate as a consequence of their existence in the degenerative environment produced by the injury. This secondary degeneration does not occur in all of the neurons at once, but affects them in a stepwise fashion related to the severity of the damage inflicted. These findings, which may be applicable to the progression of acute or chronic neuropathy, imply that neuroprotective therapy may have a beneficial effect even if there is a time lag between injury and treatment.

Animals↗

PubMed2001

Delayed glial cell death following wallerian degeneration in white matter tracts after spinal cord dorsal column cordotomy in adult rats.

The devastating consequences of spinal cord injury (SCI) result primarily from damage to long tracts in the spinal white matter. To elucidate the secondary injury processes occurring after SCI, we investigated the relationship between apoptosis and Wallerian degeneration in spinal white matter tracts. In the rat spinal cord, the corticospinal tract (CST) and the dorsal ascending tract (DAT) are separated from each other in the dorsal column and relay information in opposite directions. A dorsal column cordotomy at the eighth thoracic (T8) level simultaneously induces Wallerian degeneration in the CST caudal to and in the DAT rostral to the injury. Using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) method, we demonstrate that apoptosis occurred in areas of Wallerian degeneration in both tracts throughout the length of the cord segments studied (from T3 to T12). This delayed cell death, more apparent in the DAT, began at 7 days after injury and peaked at 14 days for the DAT and 28 days for the CST. Although a few TUNEL+ cells, slightly above the noninjury control level, were found in intact areas of both tracts, statistically significant differences in the number of TUNEL+ cells were found between the intact and the lesioned tract segments (CST, F < 0.01; DAT, F < 0.001). Within a particular spinal segment, a mean number of 64 and 939 TUNEL+ cells in the degenerating CST and DAT, respectively, were estimated stereologically at 14 days postinjury. TUNEL+ cells in degenerating tracts outnumber their intact counterparts by 3.8:1 in the CST and 4.1:1 in the DAT, although a statistically significant difference between the two was only found in the DAT at this time point (P < 0.05). Finally, we demonstrated that oligodendrocytes, the myelin-forming cells in the central nervous system, constitute at least a portion of the cells undergoing apoptosis within areas of Wallerian degeneration.

Animals↗

PubMed1993

New mouse primary retinal degeneration (rd-3).

A new mouse retinal degeneration that appears to be an excellent candidate for modeling human retinitis pigmentosa is reported. In this degeneration, called rd-3, differentiation proceeds postnatally through 2 weeks, and photoreceptor degeneration starts by 3 weeks. The rod photoreceptor loss is essentially complete by 5 weeks, whereas remnant cone cells are seen through 7 weeks. This is the only mouse homozygous retinal degeneration reported to date in which photoreceptors are initially normal. Crosses with known mouse retinal degenerations rd, Rds, nr, and pcd are negative for retinal degeneration in offspring, and linkage analysis places rd-3 on mouse chromosome 1 at 10 +/- 2.5 cM distal to Akp-1. Homology mapping suggests that the homologous human locus should be on chromosome 1q.

Age Factors↗

PubMed2002

X-linked recessive atrophic macular degeneration from RPGR mutation.

We mapped a new X-linked recessive atrophic macular degeneration locus to Xp21.1-p11.4 and show allelic involvement of the gene RPGR, which normally causes severe peripheral retinal degeneration leading to global blindness. Ten affected males whom we examined had primarily macular atrophy causing progressive loss of visual acuity with minimal peripheral visual impairment. One additional male showed extensive macular degeneration plus peripheral loss of retinal pigment epithelium and choriocapillaries. Full-field electroretinograms (ERGs) showed normal cone and rod responses in some affected males despite advanced macular degeneration, emphasizing the dissociation of atrophic macular degeneration from generalized cone degenerations, including X-linked cone dystrophy (COD1). The RPGR gene nonsense mutation G-->T at open reading frame (ORF)15+1164 cosegregated with the disease and may create a donor splice site. Identification of an RPGR mutation in atrophic maculardegeneration expands the phenotypic range associated with this gene and provides a new tool for the dissection of the relationship between clinically different retinal pathologies.

Adult↗

PubMed1998

Regulation of growth factor gene expression in degenerating motoneurons of the murine mutant wobbler: a cellular patch-sampling/RT-PCR study.

Motoneuronal degenerative diseases are characterized by their progressivity; once affected, the motoneurons remain in altered states during an intermediate phase of degeneration prior to their final disappearance. Whether this survival period coincides with active metabolic rearrangements in the affected neuron remains unknown. As a first step toward the elucidation of this question, we developed cDNA pooled samples obtained from degenerating and control motoneuron mRNA populations through cellular patch sampling and RT-PCR, using the murine wobbler mutant as a model of spinal atrophy. Hybridization of the cDNA pools to various markers of intact or degenerating motoneurons allowed us to verify the cellular specificity of the patch sampling and indicated conservation of the original mRNA population complexity. Exploration of transcriptional alterations of genes encoding growth factors thought to be involved in motoneuronal development revealed that gene expression of the neurotrophin BDNF was induced in affected motoneurons, while expression of neurotrophin-3 was present in both neuronal types. Likewise, expression of a member of the epidermal growth factor (EGF) family, the neuregulin transcript sensory motor neuron-derived factor, was detected in both control and degenerating motoneurons, while transforming growth factor alpha, the functional homolog of EGF, was present only in the affected motoneurons. Immunohistochemical detection of corresponding proteins corroborated these observations. These results demonstrate that, during the course of their degeneration, motoneurons can initiate expression of novel genes which lead to the production of molecules endowed with trophic and/or differentiative properties for the neurons themselves and their glial environment. They also validate the use of the developed cDNA pooled samples for further exploration of transcriptional alterations taking place in degenerating motoneurons.

Animals↗

PubMed1991

Direct and indirect retinal input into degenerated dorsal lateral geniculate nucleus after striate cortical removal in monkey: implications for residual vision.

We removed the striate cortex of one cerebral hemisphere in a macaque monkey, causing almost total retrograde degeneration of the corresponding dorsal lateral geniculate nucleus (dLGN) and extensive transneuronal degeneration of ganglion cells in the corresponding hemi-retina of each eye. The rare surviving geniculate projection neurons were retrogradely labelled by horseradish peroxidase (HRP) from extra-striate cortex and retinogeniculate terminals were labelled by an intraocular injection of HRP. Retinal terminals in the degenerated dLGN made synaptic contact exclusively with the dendrites of interneurons immunopositive for gamma-aminobutyric acid (GABA) in both parvocellular and magnocellular regions of dLGN. As well as being post-synaptic to retinal terminals these vesicle-containing dendrites were pre- and postsynaptic to other similar dendrites, and presynaptic to relay cells. Surviving labelled projection neurons received retinal input indirectly, via both the GABA-immunopositive interneurons and GABA-immunonegative terminals characteristic of those from the superior colliculus. In the degenerated, as opposed to the normal dLGN, about 20% of retinal terminals were GABA-immunopositive and GABA-immunoreactivity was prominently elevated in the ganglion and amacrine cell layers of the degenerated half of the retina. The optic nerve also contained numerous GABA-immunopositive axons but very few such axons were found in a normal optic nerve processed in identical manner. The surviving pathways from the retina must underlie the visual abilities that survive striate cortical removal in monkeys and human patients and may involve the degenerated dLGN as well as the mid-brain.

Animals↗