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At least 19 recordsLinked to original sources
PubMed2004

Clinical heterogeneity of neurodegeneration with brain iron accumulation (Hallervorden-Spatz syndrome) and pantothenate kinase-associated neurodegeneration.

Hallervorden Spatz syndrome (HSS), also referred to as neurodegeneration with brain iron accumulation (NBIA), is a rare inherited neurodegenerative disorder with childhood, adolescent, or adult onset. Patients with HSS/NBIA have a combination of motor symptoms in the form of dystonia, parkinsonism, choreoathetosis, corticospinal tract involvement, optic atrophy, pigmentary retinopathy, and cognitive impairment. After the recent identification of mutations in the PANK2 gene on chromosome 20p12.3-p13 in some patients with the HSS/NBIA phenotype, the term pantothenate kinase-associated neurodegeneration (PKAN) has been proposed for this group of disorders. To characterize clinically and genetically HSS/NBIA, we reviewed 34 affected individuals from 10 different families, who satisfied the inclusion criteria for NBIA. Relatives of patients who had clinical, magnetic resonance imaging (MRI), or pathological findings of NBIA were included in the study. Four patients were found to have mutations in the pantothenate kinase 2 (PANK2) gene. We compared the clinical features and MRI findings of those with and without PANK2 mutations. The presence of mutation in the PANK2 gene is associated with younger age at onset and a higher frequency of dystonia, dysarthria, intellectual impairment, and gait disturbance. Parkinsonism is seen predominantly in adult-onset patients whereas dystonia seems more frequent in the earlier-onset cases. The phenotypic heterogeneity observed in our patients supports the notion of genetic heterogeneity in the HSS/NBIA syndrome.

Adolescent↗
PubMed2004

Elevated levels of ferrimagnetic metals in foodchains supporting the Guam cluster of neurodegeneration: do metal nucleated crystal contaminants [corrected] evoke magnetic fields that initiate the progressive pathogenesis of neurodegeneration?

Elevated levels of aluminium (Al), strontium (Sr), barium (Ba), iron (Fe), manganese (Mn) cations - combined with deficiencies of magnesium (Mg)/calcium (Ca) - have been observed in the foodchains that traditionally support the Chamorro populations affected by high incidence clusters of Alzheimer (AD), Parkinson-like (PD), motor neurone diseases and multiple sclerosis on the island of Guam. Soils drawn from the cluster region demonstrated an excessive fivefold increase in 'magnetic susceptibility' readings in relation to soils from disease free adjoining regions. A multifactorial aetiological hypothesis is proposed that pivots upon the combined exposure to high levels of natural/industrial sources of ferrimagnetic/ferroelectric compounds incorporating Al, Fe, Mn, Sr, Ba (e.g., via yam/seafood consumption or exposure to world war 2 (WW2) munitions) and to low levels of Mg/Ca in all S. Pacific locations where these clusters of neurodegenerative disease have simultaneously erupted. Once gut/blood brain barrier permeability is impaired, the increased uptake of Al, Fe, Sr, Ba, or Mn into the Mg/Ca depleted brain leads to rogue metal substitutions at the Mg/Ca vacated binding domains on various enzyme/proteoglycan groups, causing a broad ranging disruption in Mg/Ca dependent systems - such as the glutamine synthetase which prevents the accumulation of neurotoxic glutamate. The rogue metals chelate sulphate, disrupting sulphated-proteoglycan mediated inhibition of crystal proliferation, as well as its regulation of the Fibroblast growth factor receptor complex which disturbs the molecular conformation of those receptors and their regulation of transphosphorylation between intracellular kinase domains; ultimately collapsing proteoglycan mediated cell-cell signalling pathways which maintain the growth and structural integrity of the neuronal networks. The depression of Mg/Ca dependent systems in conjunction with the progressive ferrimagnetisation of the CNS due to an overload of rogue ferroelectric/ferrimagnetic metal contaminants, enables 'seeding' of metal-protein crystalline arrays that can proliferate in the proteoglycan depleted brain. The resulting magnetic field emissions initiate a free radical mediated progressive pathogenesis of neurodegeneration. The co-clustering of these various types of disease in select geographical pockets around the world suggests that all of these conditions share a common early life exposure to ferromagnetic metal nucleating agents in their multifactorial aetiology. Factors such as individual genetics, the species of metal involved, etc., dictate which specific class of disease will emerge as a delayed neurotoxic response to these environmental insults.

Amyotrophic Lateral Sclerosis↗
PubMed2002

Timing of neurodegeneration and beta-amyloid (Abeta) peptide deposition in the brain of aging kokanee salmon.

Brains of kokanee salmon (Oncorhynchus nerka kennerlyi) in one of four reproductive stages (sexually immature, maturing, sexually mature, and spawning) were stained with cresyl violet and silver stain to visualize neurodegeneration. These reproductive stages correlate with increasing somatic aging of kokanee salmon, which die after spawning. Twenty-four regions of each brain were examined. Brains of sexually immature fish exhibited low levels of neurodegeneration, whereas neurodegeneration was more marked in maturing fish and greatest in spawning fish. Neurodegeneration was present in specific regions of the telencephalon, diencephalon, mesencephalon, and rhombencephalon. Pyknotic neurons were observed in all regions previously reported to be immunopositive for A beta. Regions that did not exhibit neurodegeneration during aging included the magnocellular vestibular nucleus, the nucleus lateralis tuberis of the hypothalamus, and Purkinje cells of the cerebellum, all of which also lack A beta; perhaps these regions are neuroprotected. In 14 of 16 brain areas for which data were available on both the increase in A beta deposition and pyknosis, neurodegeneration preceded or appeared more or less simultaneously with A beta production, whereas in only two regions did A beta deposition precede neurodegeneration. This information supports the hypothesis that A beta deposition is a downstream product of neurodegeneration in most brain regions. Other conclusions are that the degree of neurodegeneration varies among brain regions, neurodegeneration begins in maturing fish and peaks in spawning fish, the timing of neurodegeneration varies among brain regions, and some regions do not exhibit accelerated neurodegeneration during aging.

Aging↗
PubMed2005

Spatial and temporal characteristics of neurodegeneration after controlled cortical impact in mice: more than a focal brain injury.

The present study examined the neuropathology of the lateral controlled cortical impact (CCI) traumatic brain injury (TBI) model in mice utilizing the de Olmos silver staining method that selectively identifies degenerating neurons and their processes. The time course of ipsilateral and contralateral neurodegeneration was assessed at 6, 24, 48, 72, and 168 h after a severe (1.0 mm, 3.5 M/sec) injury in young adult CF-1 mice. At 6 hrs, neurodegeneration was apparent in all layers of the ipsilateral cortex at the epicenter of the injury. A low level of degeneration was also detected within the outer molecular layer of the underlying hippocampal dentate gyrus and to the mossy fiber projections in the CA3 pyramidal subregions. A time-dependent increase in cortical and hippocampal neurodegeneration was observed between 6 and 72 hrs post-injury. At 24 h, neurodegeneration was apparent in the CA1 and CA3 pyramidal and dentate gyral granule neurons and in the dorsolateral portions of the thalamus. Image analysis disclosed that the overall volume of ipsilateral silver staining was maximal at 48 h. In the case of the hippocampus, staining was generalized at 48 and 72 h, indicative of damage to all of the major afferent pathways: perforant path, mossy fibers and Schaffer collaterals as well as the efferent CA1 pyramidal axons. The hippocampal neurodegeneration was preceded by a significant increase in the levels of calpain-mediated breakdown products of the cytoskeletal protein alpha-spectrin that began at 6 h, and persisted out to 72 h post-injury. Damage to the corpus callosal fibers was observed as early as 24 h. An anterior to posterior examination of neurodegeneration showed that the cortical damage included the visual cortex. At 168 h (7 days), neurodegeneration in the ipsilateral cortex and hippocampus had largely abated except for ongoing staining in the cortical areas surrounding the contusion lesion and in hippocampal mossy fiber projections. Callosal and thalamic neurodegeneration was also very intense. This more complete neuropathological examination of the CCI model shows that the associated damage is much more widespread than previously appreciated. The extent of ipsilateral and contralateral neurodegeneration provides a more complete anatomical correlate for the cognitive and motor dysfunction seen in this paradigm and suggests that visual disturbances are also likely to be involved in the post-CCI neurological deficits.

Animals↗
PubMed2002

Temperature-sensitive paralytic mutants are enriched for those causing neurodegeneration in Drosophila.

Age-dependent neurodegeneration is a pathological condition found in many metazoans. Despite the biological and medical significance of this condition, the cellular and molecular mechanisms underlying neurodegeneration are poorly understood. The availability of a large collection of mutants exhibiting neurodegeneration will provide a valuable resource to elucidate these mechanisms. We have developed an effective screen for isolating neurodegeneration mutants in Drosophila. This screen is based on the observation that neuronal dysfunction, which leads to observable behavioral phenotypes, is often associated with neurodegeneration. Thus, we used a secondary histological screen to examine a collection of mutants originally isolated on the basis of conditional paralytic phenotypes. Using this strategy, we have identified 15 mutations affecting at least nine loci that cause gross neurodegenerative pathology. Here, we present a genetic, behavioral, and anatomical analysis of vacuous (vacu), the first of these mutants to be characterized, and an overview of other mutants isolated in the screen. vacu is a recessive mutation located cytologically at 85D-E that causes locomotor defects in both larvae and adults as well as neuronal hyperactivity. In addition, vacu exhibits extensive age-dependent neurodegeneration throughout the central nervous system. We also identified mutations in at least eight other loci that showed significant levels of neurodegeneration with a diverse array of neuropathological phenotypes. These results demonstrate the effectiveness of our screen in identifying mutations causing neurodegeneration. Further studies of vacu and the other neurodegenerative mutants isolated should ultimately help dissect the biochemical pathways leading to neurodegeneration.

Animals↗
PubMed2026

GWAS of Tau-Neurodegeneration Mismatch Identifies New Risk Loci for Susceptibility to Tau.

BACKGROUND: In Alzheimer's disease (AD), neurodegeneration is primarily attributed to the accumulation of tau neurofibrillary tangles. However, the distribution patterns of both tau pathology and neurodegeneration vary across different brain regions and among individuals. Moreover, multiple factors may influence the relationship between tau burden and neurodegenerative processes. Identifying the genetic architecture associated with deviation in the tau-neurodegeneration relationship can provide deeper mechanistic insights and guide the development of precision medicine strategies. METHODS: Here, I perform a genome-wide association study (GWAS) of cortical tau and thickness quantified by positron emission tomography (PET) and magnetic resonance imaging (MRI) in 794 participants from two cohorts of Alzheimer's disease Neuroimaging Initiative (ADNI) and A4. RESULTS: A GWAS was identified between the Tau/Neurodegeneration residual and two novel loci on chromosomes 7 and 14, with two SNPs (rs9323573 and rs9784993) exceeding the genome-wide significance threshold (p ≤ 5 × 10-8). SNP rs9323573 is located in STXBP6 on chromosome 14, while rs9784993 is in AKAP9 on chromosome 7, both of which were directly genotyped. The minor allele G of both SNPs (rs9323573, MAF = 0.221, p = 2.60 × 10-8; rs9784993, MAF = 0.197, p = 4.92 × 10-8) was associated with lower Tau/Neurodegeneration residuals, indicating higher-than-expected neurodegeneration given tau levels. CONCLUSION: GWAS of tau-related neurodegeneration identified two novel genetic variants in the loci AKAP9 and STXBP6 leading to higher than expected regional neurodegeneration given the tau level. Identifying genetic factors involved in tau-neurodegeneration mismatch may improve our understanding regarding the potential mechanistic downstream leading to susceptibility or resilience to tau pathology.

Humans↗
PubMed2006

Comparison of seizure phenotype and neurodegeneration induced by systemic kainic acid in inbred, outbred, and hybrid mouse strains.

We assessed inbred, outbred and hybrid mouse strains for susceptibility to seizures and neurodegeneration induced by systemic administration of kainic acid (KA). Each strain showed a unique pattern of susceptibility to seizures as assessed by the dose necessary to induce continuous tonic clonic seizures, progression through six seizure levels, the number of mice that failed to satisfy seizure criteria, and seizure-induced mortality. In general, the C57BL/6, ICR, FVB/N, and BALB/c strains were resistant to seizures while the C57BL/10, DBA/2 J, and F1 C57BL/6*CBA/J strains were vulnerable. Neuronal cell death was quantified in four subfields of the hippocampus: CA3, the hilus of the dentate gyrus, CA1, and the dentate granule cell layer. Neurodegeneration was also semiquantitatively assessed in other brain regions including the neocortex, striatum, thalamus, hypothalamus and amygdala. Although there was variability in the extent of cell death within strains, there were significant differences in the amount of hippocampal cell death between strains and also different patterns of neurodegeneration in affected brain areas. In general, the C57BL/6, C57BL/10, and F1 C57BL/6*CBA/J strains were resistant to neurodegeneration while the FVB/N, ICR and DBA/2 J strains were vulnerable. The BALB/c strain was unique in that neurodegeneration was confined to the hippocampus. Consistent with previous findings, the resistant neurodegeneration phenotype was dominant in an F1 cross of resistant and vulnerable inbred strains. Our results, using a large number of mouse strains, definitively demonstrate that a mouse strain's seizure phenotype is not related to its neurodegeneration phenotype.

Animals↗
PubMed2004

Glutamate N-methyl-D-aspartate and dopamine receptors have contrasting effects on the limbic versus the somatosensory cortex with respect to amphetamine-induced neurodegeneration.

The roles that glutamate N-methyl-D-aspartate (NMDA) and dopamine D1-like and D2-like receptors play in the cortical neurotoxicity occurring in rats exposed to multiple doses of amphetamine (AMPH) for 2 days was evaluated. Neurodegeneration in rats that did not become hyperthermic during AMPH exposure was quantified by counting isolectin B4-labeled phagocytic microglia and Fluoro-Jade (F-J)-labeled neurons in the somatosensory parietal cortex, piriform cortex and posterolateral cortical amygdaloid nucleus (PLCo). The NMDA receptor antagonist, dizocilpine (0.63 mg/kg day) blocked AMPH-induced neurodegeneration in the somatosensory cortex. However, it did not affect degeneration in the piriform cortex and PLCo indicating that limbic degeneration was not NMDA-mediated. The dopamine antagonists, eticlopride (D2/3, 0.25 mg/kg day) and SCH-23390 (D1, 0.25 mg/kg day), blocked the stereotypic behavior and neurodegeneration in the somatosensory cortex. However, eticlopride had a lesser protective effect in the limbic regions. As well, the dopamine D2/D3 agonist quinpirole (1.5 mg/kg day) protected against cortical neurodegeneration when it was given during AMPH exposure and continued until sacrifice. The dopamine D1 agonist (SKF-38393, 12.5 mg/kg day) had no significant effect on neurodegeneration. These data indicate that there are significant differences in NMDA and dopamine D2 modulation of AMPH-induced neurodegeneration in the somatosensory cortex compared to the limbic cortices, and limbic cortical degeneration is not necessarily dependent on excessive stimulation of NMDA receptors as it is in the somatosensory cortex. Although excessive dopamine receptor stimulation during amphetamine exposure may trigger the neurodegenerative processes, continued D2 stimulation after AMPH exposure is neuroprotective in the cortex.

Amphetamine↗
PubMed2006

TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model.

BACKGROUND: Previous studies have demonstrated reexpression of cell-cycle markers within postmitotic neurons in neurodegenerative tauopathies, including Alzheimer's disease (AD). However, the critical questions of whether cell-cycle activation is causal or epiphenomenal to tau-induced neurodegeneration and which signaling pathways mediate cell-cycle activation in tauopathy remain unresolved. RESULTS: Cell-cycle activation accompanies wild-type and mutant tau-induced neurodegeneration in Drosophila, and genetically interfering with cell-cycle progression substantially reduces neurodegeneration. Our data support a role for cell-cycle activation downstream of tau phosphorylation, directly preceding apoptosis. We accordingly show that ectopic cell-cycle activation leads to apoptosis of postmitotic neurons in vivo. As in AD, TOR (target of rapamycin kinase) activity is increased in our model and is required for neurodegeneration. TOR activation enhances tau-induced neurodegeneration in a cell cycle-dependent manner and, when ectopically activated, drives cell-cycle activation and apoptosis in postmitotic neurons. CONCLUSIONS: TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model, identifying TOR and the cell cycle as potential therapeutic targets in tauopathies and AD.

Animals↗
PubMed2006

Antidepressant-mediated reversal of abnormal behavior and neurodegeneration in mice following olfactory bulbectomy.

Olfactory bulbectomy is an established animal model of depression that has been mostly investigated in rats. As in human major depression, bulbectomy induces behavioral alterations that can be ameliorated by chronic antidepressant treatment. Furthermore, bulbectomy in rats is known to induce neurodegeneration in some brain areas. The aim of the present study was to evaluate patterns of behavioral alterations and neurodegeneration, and their drug-induced reversibility, in bulbectomized mice. Our results reveal that in mice bulbectomy increases locomotor activity and induces deficits in the passive avoidance test, comparable to the effects seen in rats. Bulbectomy also induced neuronal degeneration, visualized by incorporation of Fluoro-Jade B, in the piriform cortex and the posterolateral cortical amygdaloid nucleus (PLCo). Chronic treatment with the antidepressant amitriptyline protected neurons in both areas and efficiently reversed abnormal locomotor activity induced by bulbectomy. Treatment with citalopram was effective in reversing the behavioral deficits induced by bulbectomy, but did not protect against neurodegeneration. Our data indicate significant overlap between mice and rats in terms of behavioral alterations and neurodegeneration following olfactory bulbectomy. However, there are differences in drug-mediated reversibility of neurodegeneration suggesting that neurodegeneration and protection may be "second-order" features in this animal model of depression. This may also be relevant in the context of studies using genetically altered mice.

Amitriptyline↗
PubMed1998

Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: A perspective on the contributions of apoptosis and necrosis.

In the human brain and spinal cord, neurons degenerate after acute insults (e.g., stroke, cardiac arrest, trauma) and during progressive, adult-onset diseases [e.g., amyotrophic lateral sclerosis, Alzheimer's disease]. Glutamate receptor-mediated excitotoxicity has been implicated in all of these neurological conditions. Nevertheless, effective approaches to prevent or limit neuronal damage in these disorders remain elusive, primarily because of an incomplete understanding of the mechanisms of neuronal death in in vivo settings. Therefore, animal models of neurodegeneration are crucial for improving our understanding of the mechanisms of neuronal death. In this review, we evaluate experimental data on the general characteristics of cell death and, in particular, neuronal death in the central nervous system (CNS) following injury. We focus on the ongoing controversy of the contributions of apoptosis and necrosis in neurodegeneration and summarize new data from this laboratory on the classification of neuronal death using a variety of animal models of neurodegeneration in the immature or adult brain following excitotoxic injury, global cerebral ischemia, and axotomy/target deprivation. In these different models of brain injury, we determined whether the process of neuronal death has uniformly similar morphological characteristics or whether the features of neurodegeneration induced by different insults are distinct. We classified neurodegeneration in each of these models with respect to whether it resembles apoptosis, necrosis, or an intermediate form of cell death falling along an apoptosis-necrosis continuum. We found that N-methyl-D-aspartate (NMDA) receptor- and non-NMDA receptor-mediated excitotoxic injury results in neurodegeneration along an apoptosis-necrosis continuum, in which neuronal death (appearing as apoptotic, necrotic, or intermediate between the two extremes) is influenced by the degree of brain maturity and the subtype of glutamate receptor that is stimulated. Global cerebral ischemia produces neuronal death that has commonalities with excitotoxicity and target deprivation. Degeneration of selectively vulnerable populations of neurons after ischemia is morphologically nonapoptotic and is indistinguishable from NMDA receptor-mediated excitotoxic death of mature neurons. However, prominent apoptotic cell death occurs following global ischemia in neuronal groups that are interconnected with selectively vulnerable populations of neurons and also in nonneuronal cells. This apoptotic neuronal death is similar to some forms of retrograde neuronal apoptosis that occur following target deprivation. We conclude that cell death in the CNS following injury can coexist as apoptosis, necrosis, and hybrid forms along an apoptosis-necrosis continuum. These different forms of cell death have varying contributions to the neuropathology resulting from excitotoxicity, cerebral ischemia, and target deprivation/axotomy. Degeneration of different populations of cells (neurons and nonneuronal cells) may be mediated by distinct or common causal mechanisms that can temporally overlap and perhaps differ mechanistically in the rate of progression of cell death.

Animals↗
PubMed2003

RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila.

Fragile X syndrome carriers have FMR1 alleles, called premutations, with an intermediate number of 5' untranslated CGG repeats between patients (>200 repeats) and normal individuals (<60 repeats). A novel neurodegenerative disease has recently been appreciated in some premutation carriers. As no neurodegeneration is seen in fragile X patients, who do not express FMR1, we hypothesize that lengthened rCGG repeats of the premutation transcript may lead to neurodegeneration. Here, using Drosophila melanogaster, we show that 90 rCGG repeats alone are sufficient to cause neurodegeneration. This phenotype is neuron specific and rCGG repeat dosage sensitive. Although devoid of mutant protein, this neurodegeneration exhibits neuronal inclusion bodies that are Hsp70 and ubiquitin positive. Overexpression of Hsp70 could suppress the neurodegeneration. These results demonstrate that neurodegenerative phenotype associated with fragile X premutation is indeed caused by the lengthened rCGG repeats and provide the first in vivo experimental demonstration of RNA-mediated neurodegeneration.

Animals↗
PubMed2005

Lack of a gender difference in post-traumatic neurodegeneration in the mouse controlled cortical impact injury model.

Recent studies using a mouse model of weight-drop-induced "diffuse" traumatic brain injury (TBI) have demonstrated a substantial gender difference in the time course and magnitude of post-traumatic neurodegeneration following a severe level of injury. The time of maximal damage, as assessed by the de Olmos aminocupric silver staining method, occurred at 72 h in male mice, whereas the peak of neurodegeneration was not observed until 14 days in females and was less in magnitude compared to males. This difference, favoring females, has been postulated to relate to the neuroprotective actions of estrogen and progesterone. In the presently reported experiments, we compared the time course and peak of neurodegeneration in male and female mice after a severe level of "focal" controlled cortical impact (CCI; 1 mm, 3.5 m/sec) TBI using the same strain (CF-1) and weight (29-31 g) as employed in the "diffuse" TBI study. The volume of silver staining was measured using image analysis methods at 24, 48, and 72 h, and 1, 2 and 4 weeks. In male and female mice, a significant increase in neurodegeneration was observed at 24 h, and the volume was not significantly different between the two genders. In both gender groups, the maximal neurodegeneration was seen at 48 h after injury. Although the female mice exhibited a trend toward higher mean volumes of silver staining, this difference was not significantly different compared to males. Furthermore, the rate of resolution of staining between 48 h and 4 weeks was similar. However, injured females still exhibited a significantly higher volume of staining compared to sham, non-injured females at 4 weeks, whereas the difference in staining volume between sham and injured males was no longer significant at that time point. These results show that, following a "focal" CCI, there is no gender difference that favors females, in contrast to that seen with the "diffuse" injury paradigm. The disparity between the effects of gender in the two models may be due to the fact that, in the "focal" CCI model, the timing of post-traumatic neurodegeneration is significantly more rapid than that seen in the "diffuse" model, which may overwhelm the neuroprotective effects of estrogen and progesterone and obscure the appearance of a gender difference.

Animals↗
PubMed2006

Differential susceptibility to striatal neurodegeneration induced by quinolinic acid and kainate in inbred, outbred and hybrid mouse strains.

In mice, the genetic background determines susceptibility to hippocampal neurodegeneration induced by the excitotoxin kainic acid (KA). If genetic background plays as significant a role in the striatum, the area most affected in Huntington's disease (HD), it is important to characterize intrinsic differences in neuronal susceptibility in mouse strains used in HD models. This study was performed to investigate whether strain differences of different HD mouse models are determinants of striatal resistance to excitotoxicity. We conducted a survey of the susceptibility of striatal neurons to neurodegeneration induced by quinolinic acid and KA in six inbred, two outbred and two F1 hybrid (resistant*vulnerable) strains. These are the same strains in which we have assessed vulnerability to KA-induced hippocampal neurodegeneration. We found significant strain differences in response to both excitotoxins and, for the most part, the strain-dependent patterns of susceptibility to quinolinic acid and KA were similar and comparable to those previously found with KA-induced hippocampal neurodegeneration. There were some incongruities, suggesting that the genetic determinants may be different for the two forms of excitotoxicity or that there are important interacting factors. For example, the F1 hybrid strains exhibited neurodegeneration similar to their vulnerable parent, indicating that the vulnerable phenotype is dominant. This is in contrast to KA-induced hippocampal neurodegeneration, where F1 hybrids exhibit the resistant phenotype. These results are also of significance with regard to the issue of region-specific vulnerability in the context of different diseases in which genetic modifiers affect age of onset and/or disease progression.

Animals↗
PubMed2005

Human expanded polyglutamine androgen receptor mutants in neurodegeneration as a novel ligand target.

Androgen receptor (AR) plays key roles in various biological events, including pathological processes such as prostate cancer, androgen-insensitive syndrome, and spinal and bulbar muscular atrophy (SBMA). SBMA is caused by mutation of the expanded polyglutamine (polyQ) stretches in the AR gene. Recently, we established a Drosophila SBMA model that expresses the expanded polyQ hAR mutant in eyes, which monitors neurodegeneration as a rough eye phenotype. In addition, we showed that androgen binding to the mutant hAR causes structural alterations, leading to the onset of neurodegeneration in the fly eyes. In the present study, we examined whether the ligand-induced neurodegeneration via the hAR mutant is coupled with the known ligand-induced transactivation function of hAR. By testing several known AR antagonists and several of their structure-related compounds, we unexpectedly found that none of the AR ligands antagonized the hAR mutant neurodegeneration function, and surprisingly, compound 4-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-trifluoromethylbenzonitrile (RU56279) was more potent in inducing neurodegeneration. However, in vitro and in vivo mammalian assays showed that RU56279 exhibited the expected antagonistic activity with the same potency as those of the other compounds. Thus, these findings suggest the presence of a novel ligand-induced function of the polyQ hAR mutant in neurodegeneration that could not be prevented by known antagonists for the hAR transactivation function.

Androgen Antagonists↗
PubMed2002

Pathways leading to apoptotic neurodegeneration following trauma to the developing rat brain.

Trauma triggers diffuse apoptotic neurodegeneration in the developing rat brain. To explore the pathogenesis of this phenomenon we investigated the involvement of three possible mechanisms: death receptor activation, activation of the intrinsic apoptotic pathway by cytochrome c release into the cytoplasm, and changes in trophic support provided by endogenous neurotrophins. We detected a decrease in the expression of bcl-2 and bcl-x(L), two antiapoptotic proteins that decrease mitochondrial membrane permeability, an increase in cytochrome c immunoreactivity in the cytosolic fraction, and an activation of caspase-9 in brain regions which show apoptotic neurodegeneration following percussion brain trauma in 7-day-old rats. Increase in the expression of the death receptor Fas was revealed by RT-PCR analysis, Western blotting, and immunohistochemistry, as was activation of caspase-8 in cortex and thalamus. Apoptotic neurodegeneration was accompanied by an increase in the expression of BDNF and NT-3 in vulnerable brain regions. The pancaspase inhibitor z-VAD.FMK ameliorated apoptotic neurodegeneration with a therapeutic time window of up to 8 h after trauma. These findings suggest involvement of intrinsic and extrinsic apoptotic pathways in neurodegeneration following trauma to the developing rat brain. Upregulation of neurotrophin expression may represent an endogenous mechanism that limits this apoptotic process.

Amino Acid Chloromethyl Ketones↗