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PubMed2004

N-alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) suppresses neuritic degeneration caused by different experimental paradigms including in vitro Wallerian degeneration.

Accumulating evidence indicates that neurite degeneration occurs via a distinct mechanism from somal death programs. We have previously shown that neuritic ATP level in sympathetic neurons decreases, whereas somal ATP level remains unaltered during degeneration caused by the microtubule-disrupting agent, vinblastine. Moreover, caspase activation occurs only in cell soma, supporting the view of somal apoptosis and neuritic necrosis. Therefore, the ATP level of neurites is crucial for their degeneration; it appears to correlate with membrane blebbing or beading which precedes late whole fragmentation of neurites under these conditions. Based on these metabolic and morphological criteria, we have tested the effects of various protease inhibitors on vinblastine-induced neurite degeneration in superior cervical ganglia from neonatal mice. Among agents tested, N-alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK), the trypsin-like serine protease inhibitor, but not N-p-tosyl-L-phenylalanine chloromethyl ketone (TPCK), the chymotrypsin-like serine protease inhibitor, protected sympathetic neurites from beading formation, neuritic fragmentation and a decrease in their ATP level. The commitment time for the saving effect of TLCK occurred around 7 h following treatment with vinblastine, at a time point after microtubule degradation (2 h) and before massive beading formation (later than 12 h). Moreover, TLCK was also capable of suppressing Wallerian degeneration in culture and neuritic degeneration following withdrawal of NGF in a dose-dependent manner. These results strongly suggest that TLCK intervenes in a common step in the cascade of neuritic degeneration caused by these different experimental paradigms and provides a helpful clue for identifying such a molecular step.

Adenosine Triphosphate↗
PubMed1998

Rhodopsin mutations as the cause of retinal degeneration. Classification of degeneration phenotypes in the model system Drosophila melanogaster.

Insight into the molecular basis of inherited photoreceptor cell degeneration has been rapidly evolving during the last decade. The Drosophila Rh1 rhodopsin gene was the first gene shown to cause retinal degeneration when mutated. Many more degeneration-causing mutations in genes encoding rhodopsin and other photoreceptor proteins have been isolated since then in both, Drosophila and humans. To date some 70 mutations of the Drosophila Rh1 gene have been isolated, most of them have been characterized at the molecular level, and more than 60% of them cause retinal degeneration. This review lists the known Rh1 mutations that cause retinal degeneration up to April 1998, gives an overview on the ultrastructural and biochemical correlates of photoreceptor cell degeneration, and suggests a system for the classification of degeneration-causing Rh1 mutations.

Amino Acid Sequence↗
PubMed2005

Effect of steroidal and non-steroidal drugs on the microglia activation pattern and the course of degeneration in the retinal degeneration slow mouse.

BACKGROUND: In hereditary retinal degeneration, microglia cells become activated, migrate through the outer nuclear layer (ONL) and accumulate in the subretinal space. Although this inflammatory process is not likely to be responsible for the onset of photoreceptor apoptosis, cytotoxic substances secreted by activated microglia could potentially accelerate and perpetuate the degenerative process. Anti-inflammatory drugs have been shown to modulate the microglia response in neurodegenerative disorders and potentially ameliorate the disease progression in various animal model systems. In this study we wanted to test the impact of the most commonly used anti-inflammatory drugs (acetylsalicylate and prednisolone) on the microglia activation pattern, the rate of caspase-3-dependent photoreceptor apoptosis and the course of the degeneration in the retinal degeneration slow (rds) mouse retina. METHODS: 169 pigmented rds mice and 30 CBA wild-type mice were used for this study. The treatment groups were injected daily with either acetylsalicylate (200 mg/kg) or prednisolone (2 mg/kg) i.p. from day 0 up to 3 months. Animals were sacrificed at days 10, 14, 16, 18, 20, 30, 40, 60 and 90. Cryoprotected frozen sections were immunostained with F4/80 and cleaved caspase-3 antibodies. The main outcome measures were the total microglia count in the subretinal space, the total cleaved caspase-3-positive cells in the ONL and the averaged number of photoreceptor rows in the midperipheral retina. RESULTS: Neither acetylsalicylate nor prednisolone reduced subretinal microglia accumulation in the rds mouse degeneration model. Moreover, they aggravated migration and accumulation in the early time course. The apoptotic cascade started earlier and was more pronounced in both treatment groups compared to the control group. The pace of retinal degeneration was not reduced in the treatment groups compared to the untreated control. In contrast, acetylsalicylate did significantly accelerate the photoreceptor cell degeneration in comparison to the prednisolone (p < 0.001) and to the control group (p < 0.001). CONCLUSIONS: Acetylsalicylate and prednisolone do not decrease the microglia response in the rds mouse and are not neuroprotective. More research is needed to clarify the molecular mechanisms which lead to photoreceptor cell death and to elucidate the complex role of microglia in inherited retinal degeneration.

Animals↗
PubMed1985

Degeneration of thalamic neurons in "Purkinje cell degeneration" mutant mice. II. Cytology of neuron loss.

The cytology of thalamocortical relay neuron degeneration in the ventral medial geniculate nucleus (vMG) of mice homozygous for the autosomal recessive Purkinje cell degeneration (pcd) mutation has been studied by light and electron microscopy. More limited sampling of the submedial and mediodorsal nuclei suggested that cytological alterations in the vMG were typical of all degenerating thalamic nuclei. The number of vMG neurons in pcd mutants was comparable to controls at and prior to postnatal day 40 (P40). By P60 seventy percent, and by P90 approximately 90%, of the original complement of vMG neurons had degenerated in mutant mice. At P30, the general cytological organization of vMG neurons closely resembled that of neurons in littermate (+/+ or +/pcd) controls, but neurons in mutants were distinguished by the presence of small aggregates of fine granules (approximately 9 nm in diameter) that were commonly associated with otherwise normal cisternae of rough endoplasmic reticulum; neither the number nor the size of these granular aggregates increased in older mutants. By P50 cytoplasmic organelles were curiously distributed in more severely affected neurons: large areas of cytoplasm were occupied exclusively by polysomes, while profiles of endoplasmic reticulum and the Golgi apparatus appeared to be reduced. Before frank degenerative changes were apparent (at P50), all classes of synaptic terminals identified in normal mice were found to have made morphologically normal synaptic contacts on mutant vMG neuron dendrites. In contrast to the homologous nuclear complex in the cat, presynaptic dendrites were not apparent in synaptic glomeruli in wild-type or mutant murine vMG. Cytopathological alterations in the neuropil of P50 and older mutants were dominated by degenerating dendritic profiles; there was no evidence that the loss of thalamic neurons in pcd mutants was associated with synaptic agenesis or dysgenesis or the prior or concurrent degeneration of afferent synaptic terminals.

Aging↗
PubMed2005

Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: a model for macular degeneration.

Macular degeneration is a heterogeneous group of disorders characterized by photoreceptor degeneration and atrophy of the retinal pigment epithelium (RPE) in the central retina. An autosomal dominant form of Stargardt macular degeneration (STGD) is caused by mutations in ELOVL4, which is predicted to encode an enzyme involved in the elongation of long-chain fatty acids. We generated transgenic mice expressing a mutant form of human ELOVL4 that causes STGD. In these mice, we show that accumulation by the RPE of undigested phagosomes and lipofuscin, including the fluorophore, 2-[2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E-octatetraenyl]-1-(2-hyydroxyethyl)-4-[4-methyl-6-(2,6,6,-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E-hexatrienyl]-pyridinium (A2E) is followed by RPE atrophy. Subsequently, photoreceptor degeneration occurs in the central retina in a pattern closely resembling that of human STGD and age-related macular degeneration. The ELOVL4 transgenic mice thus provide a good model for both STGD and dry age-related macular degeneration, and represent a valuable tool for studies on therapeutic intervention in these forms of blindness.

Animals↗
PubMed1992

Calcium channel blockers inhibit retinal degeneration in the retinal-degeneration-B mutant of Drosophila.

Light accelerates degeneration of photoreceptor cells of the retinal degeneration B (rdgB) mutant of Drosophila. During early stages of degeneration, light stimuli evoke spikes from photoreceptors of the mutant fly; no spikes can be recorded from photoreceptors of the wild-type fly. Production of spike potentials from mutant photoreceptors was blocked by diltiazem, verapamil hydrochloride, and cadmium. Little, if any, effect of the (-)-cis isomer or (+)-cis isomer of diltiazem on the light response was seen. Further, the (+)-cis isomer was approximately 50 times more effective than the (-)-cis isomer in blocking the Ca2+ spikes, indicating that diltiazem action on the rdgB eye is mediated by means of blocking voltage-sensitive Ca2+ channels, rather than by blocking the light-sensitive channels. Application of the Ca(2+)-channel blockers (+)-cis-diltiazem and verapamil hydrochloride to the eyes of rdgB flies over a 7-day period largely inhibited light-dependent degeneration of the photoreceptor cells. Pulse labeling with [32P]phosphate showed much greater incorporation into eye proteins of [32P]phosphate in rdgB flies than in wild-type flies. Retarding the light-induced photoreceptor degeneration in the mutant by Ca(2+)-channel blockers, thus, suggests that toxic increase in intracellular Ca2+ by means of voltage-gated Ca2+ channels, possibly secondary to excessive phosphorylation, leads to photoreceptor degeneration in the rdgB mutant.

Action Potentials↗
PubMedDate not supplied

Degeneration of posterior column nucleus, inferior olivary nucleus and cerebellar cortex: system degeneration of paraneoplastic disease?

Degeneration of the posterior column nucleus, inferior olive, and cerebellar cortex is reported in a cancer patient. A 70-year-old man developed an ataxic gait and rapidly progressive disturbance of deep sensation over six months, followed by an abasic state. Early well-differentiated tubular adenocarcinoma was detected and total gastrectomy was performed. He died due to pulmonary tuberculosis about two years and nine months after the operation. Degeneration of the posterior column nuclei was found, explaining the disturbance of deep sensation noted in the clinical course, although there were few changes in the peripheral nerves, dorsal root ganglia, and spinal cord. Degeneration of the inferior olive and cerebellar corte was also found. Metastatic small cell carcinoma was present in the right pulmonary hilar and paratracheal lymph nodes at autopsy without any detectable primary focus. There was neither recurrence nor metastasis of the gastric carcinoma. This is the first case report of this type of central nervous system degeneration in a cancer patient, and its pathogenesis and etiology remain obscure. We discuss whether system degeneration or paraneoplastic degeneration was the etiology.

Adenocarcinoma↗
PubMed1997

Differential expression of photoreceptor-specific proteins during disease and degeneration in the progressive rod-cone degeneration (prcd) retina.

Progressive rod-cone degeneration (prcd) is a late-onset hereditary retinal degeneration characterized by normal development of photoreceptors prior to degeneration and death of visual cells. We reported previously that expression of opsin mRNA and protein decreases prior to visual cell degeneration. To examine the specificity of this reduction, we have used immunocytochemistry to correlate photoreceptor-specific protein expression with visual cell disease progression. Eyes from light-adapted age-matched control and prcd-affected dogs were fixed in paraformaldehyde, embedded in diethylene glycol distearate (DGD) wax, and reacted with antibodies specific to interphotoreceptor retinoid-binding protein (IRBP), S-antigen, opsin, phosducin, gamma-phosphodiesterase (gamma-PDE), and beta 1-transducin. While IRBP expression did not change with disease progression, immunoreactivity to other proteins varied. For S-antigen and opsin, immunoreactivity decreased dramatically with the transition from photoreceptor disease to degeneration; gamma-PDE immunolabeling in rods also decreased, but the reduction was less abrupt. However, for two other proteins (phosducin and beta 1-transducin), immunoreactivity increased initially and was redistributed (particularly to the rod outer segment) in early disease (stage 1). Our results show that there is a differential expression of photoreceptor-specific proteins with disease and degeneration that is not uniform for all the gene products examined; expression can be decreased, altered in distribution or remain unchanged. It is clear that the decrease of opsin expression described previously is not an isolated phenomenon in the progression of prcd, but is part of a more generalized degenerative process which eventually culminates in cell death.

Animals↗
PubMed1990

[Visual function of cynomolgus monkeys with macula degeneration and peripheral retinal degeneration].

Using the simplified method for judging visual function of the cynomolgus monkey that was established by the present authors (Suzuki et al., 1988), forty-four cynomolgus monkeys with normal ophthalmoscopic findings, eleven monkeys with macula degeneration and thirteen monkeys with peripheral retinal degeneration were examined for their visual function. It was demonstrated that the monkeys with macula degeneration were inferior in their visual function to the monkeys with normal fundus. In addition, the degree of visual function varied with the degree of macula degeneration. The monkeys with peripheral retinal degeneration showed about the same degree in their visual function as the monkeys with normal fundus.

Animals↗
PubMed1979

Neurochemical and morphological consequences of axon terminal degeneration in cerebellar deep nuclei of mice with inherited Purkinje cell degeneration.

The concentrations of free amino acids and the activities of transmitter-related enzymes, glutamic acid decarboxylase (GAD), choline acetylase (ChAC) and GABA-transaminase (GABA-t) were measured in cerebellar cortex and deep cerebellar nuclei from the mouse mutant Purkinje cell degeneration (pcd) at various times before and after Purkinje cell loss. Axosomatic synapses on target cells in pcd deep nuclei were quantified by electron microscopy during and after degeneration. The concentration of GABA (nmol/mg wet weight), the Purkinje cell transmitter, was normal in pcd cerebellar cortex and deep nuclei before onset of Purkinje cell degeneration on postnatal day 15. Just after the major period of Purkinje cell loss in cerebellar cortex, GABA concentration was unchanged in the cortical layers but fell to 50% of normal values in the deep nuclei of pcd animals killed either by decapitation or by microwave irradiation. No other measured free amino acid decreased. There were no long-term increases following Purkinje cell degeneration in the concentration of any transmitter amino acids or related enzymes, GAD, ChAC or GABA-t, and thus no indication of axonal sprouting reactions. Progressive losses occurred in wet weight and protein and in activity of GABA-t in both the cerebellar cortex and the deep nuclei of pcd animals. Electron microscopic analysis indicated that Purkinje cell axon terminals contact 30% or more of the somatic surface of principal neurons of the lateral nucleus of the normal cerebellum, but only about 2% of the corresponding sites in the pcd cerebellum. Glial leaflets, rather than other synaptic terminals take their place. Axon terminals may degenerate earlier than Purkinje somata in the pcd disease.

4-Aminobutyrate Transaminase↗
PubMed1987

Retinal degenerations in the dog: IV. Early retinal degeneration (erd) in Norwegian elkhounds.

A new early onset hereditary retinal degeneration is characterized in Norwegian elkhound dogs. This disease, termed early retinal degeneration (erd), was studied in 10 affected dogs, from 30 days- to 7 years old, clinically, by electroretinography, and by light- and electron-microscopic morphology. Control studies were performed on 49 non-affected dogs. Affected dogs are initially nightblind, and become totally blind between 12- and 18 months of age. The postnatal development of their rod and cone photoreceptors is abnormal both structurally and functionally. Morphologically, rod and cone inner- and outer-segment growth occurs but appears uncoordinated. Adjacent rods become very disparate in the size and proportions of their inner- and outer segments. Prominent villiform processes extend from the inner segments of rods and, to a lesser extent, cones. Synaptic terminals of rods and cones fail to develop properly. The b-wave of the electroretinogram fails to develop and the electroretinogram (ERG) remains a-wave-dominated. Subsequent to these abnormalities of development, the rods and cones degenerate, rapidly at first and later more gradually. In normal dogs, development of the ERG a- and b-waves is shown to follow, respectively, morphologic development of the photoreceptor outer segments and synaptic terminals. Similarly the abnormal development and subsequent degeneration of photoreceptor outer segments and synaptic terminals in affected dogs, correspond in time course to development and degeneration of the ERG a- and b-waves.

Aging↗
PubMed2006

NAD(+) and axon degeneration revisited: Nmnat1 cannot substitute for Wld(S) to delay Wallerian degeneration.

The slow Wallerian degeneration protein (Wld(S)), a fusion protein incorporating full-length nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1), delays axon degeneration caused by injury, toxins and genetic mutation. Nmnat1 overexpression is reported to protect axons in vitro, but its effect in vivo and its potency remain unclear. We generated Nmnat1-overexpressing transgenic mice whose Nmnat activities closely match that of Wld(S) mice. Nmnat1 overexpression in five lines of transgenic mice failed to delay Wallerian degeneration in transected sciatic nerves in contrast to Wld(S) mice where nearly all axons were protected. Transected neurites in Nmnat1 transgenic dorsal root ganglion explant cultures also degenerated rapidly. The delay in vincristine-induced neurite degeneration following lentiviral overexpression of Nmnat1 was significantly less potent than for Wld(S), and lentiviral overexpressed enzyme-dead Wld(S) still displayed residual neurite protection. Thus, Nmnat1 is significantly weaker than Wld(S) at protecting axons against traumatic or toxic injury in vitro, and has no detectable effect in vivo. The full protective effect of Wld(S) requires more N-terminal sequences of the protein.

Animals↗
PubMed1973

Hypertrophic olivary degeneration and Purkinje cell degeneration in a case of long-standing head injury.

A case is reported of a 52 year old man who sustained a head injury and survived for three years and two months in coma. He was subsequently shown to have severe brain stem damage, with a bilateral lesion of the central tegmental tract and bilateral hypertrophic olivary degeneration, associated with a widespread loss of Purkinje cells in the cerebellar cortex. Hypertrophic olivary degeneration is considered to be a trans-synaptic change associated with a lesion of the central tegmental tract, which in this case was thought to be due to primary shearing injury of the brain stem involving the superior cerebellar peduncles. It is suggested that, as a consequence of long survival, Purkinje cell degeneration represents further trans-synaptic changes, the result of neuronal degeneration in the hypertrophied inferior olivary nuclei and in the dentate nuclei. A chain or `circuit' of degenerated neurones is thereby produced.

Autopsy↗
PubMed1993

Structural changes of the interphotoreceptor matrix in an inherited retinal degeneration: a lectin cytochemical study of progressive rod-cone degeneration.

PURPOSE: In the retinal disorder progressive rod-cone degeneration (prcd) in miniature poodle dogs, the photoreceptor layer degenerates slowly in the course of 5 to 7 years. Components of the interphotoreceptor matrix form a continuous extracellular lattice around photoreceptors. The purpose was to study the photoreceptor cell-matrix interactions during the disease and degeneration phases. Because degeneration rate was slower in cones, the authors also wanted to investigate whether there was a link between the degeneration and the photoreceptor-specific interphotoreceptor matrix domains. METHODS: Rod- and cone-specific interphotoreceptor matrix domains were examined during two periods: before morphological signs of disease had appeared and during the degenerative stages. Two lectin probes were used; wheat germ agglutinin and peanut agglutinin. By their affinity for terminal carbohydrates, the lectins visually separated the two photoreceptor-specific domains and allowed follow-up of the fate of the rod and cone matrices separately. RESULTS: Before and during the course of disease, the lectin distribution in rod and cone domains remained normal, however, in the degenerative phase of the disease, there were structural changes in the matrix domains. The matrix connections between the individual domains was disrupted and single domains were formed. Cone domains and, to a lesser degree rod domains, were thickened around the inner and outer segments. CONCLUSIONS: The changes occurring in the photoreceptor-specific domains were indicative of structural adaptation to cell death and to degenerative conditions. There was no evidence of an active involvement of the interphotoreceptor matrix components studied in the disease process.

Animals↗