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1.
Polyglutamine expansion mutations in specific proteins underlie the pathogenesis of a group of progressive neurodegenerative disorders, including Huntington’s disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and several spinocerebellar ataxias. The different mutant proteins share ubiquitous expression and abnormal proteostasis, with misfolding and aggregation, but nevertheless evoke distinct patterns of neurodegeneration. This highlights the relevance of the full protein context where the polyglutamine expansion occurs and suggests different interactions with the cellular proteostasis machinery. Molecular chaperones are key elements of the proteostasis machinery and therapeutic targets for neurodegeneration. Here, we provide a focused review on Hsp90, Hsp70, and their co-chaperones, and how their genetic or pharmacological modulation affects the proteostasis and disease phenotypes in cellular and animal models of polyglutamine disorders. The emerging picture is that, in principle, Hsp70 modulation may be more amenable for long-term treatment by promoting a more selective clearance of mutant proteins than Hsp90 modulation, which may further decrease the necessary wild-type counterparts. It seems, nevertheless, unlikely that a single Hsp70 modulator will benefit all polyglutamine diseases. Indeed, available data, together with insights from effects on tau and alpha-synuclein in models of Alzheimer’s and Parkinson’s diseases, indicates that Hsp70 modulators may lead to different effects on the proteostasis of different mutant and wild-type client proteins. Future studies should include the further development of isoform selective inhibitors, namely to avoid off-target effects on Hsp in the mitochondria, and their characterization in distinct polyglutamine disease models to account for client protein-specific differences. 相似文献
2.
Dopaminergic activity is expected to be altered in patients with Huntington’s disease (HD) and be related to factors like
duration and severity of illness or patients’ specific symptomatology like dementia, depression, or psychotic features. We
assessed plasma homovanillic acid (pHVA) and plasma prolactin (pPRL), two correlates of dopaminergic activity, in 116 subjects
with CAG repeats expansion in the HD gene, 26 presymptomatic (18 females) and 90 with overt symptomatology (43 females). Patients
were evaluated using the Unified HD Rating Scale and the Total Functional Capacity Scale. Presence of dementia, depression,
and psychotic features were also assessed. The age range of the patients was 22–83 years, duration of illness from 0.5 to
27 years, and CAG repeat number from 34 to 66. A group of 60 age and sex matched healthy subjects served as control group.
Plasma PRL in subjects at risk and in neuroleptic-free patients, evaluated separately for males and females, did not differ
from controls. Plasma HVA levels did not differ from controls in the group of presymptomatic subjects, but were significantly
higher in the patients group. This increase was positively associated mainly with severity of illness and functional capacity
of the patients, and not with presence of depression or dementia. Plasma HVA levels may be proven to be a peripheral index
of disease progression. Reducing dopaminergic activity may have not only symptomatic, but also neuroprotective effects in
HD. 相似文献
3.
Koichi Wakabayashi Kunikazu Tanji Saori Odagiri Yasuo Miki Fumiaki Mori Hitoshi Takahashi 《Molecular neurobiology》2013,47(2):495-508
The histopathological hallmark of Parkinson’s disease (PD) is the presence of fibrillar aggregates referred to as Lewy bodies (LBs), in which α-synuclein is a major constituent. Pale bodies, the precursors of LBs, may serve the material for that LBs continue to expand. LBs consist of a heterogeneous mixture of more than 90 molecules, including PD-linked gene products (α-synuclein, DJ-1, LRRK2, parkin, and PINK-1), mitochondria-related proteins, and molecules implicated in the ubiquitin–proteasome system, autophagy, and aggresome formation. LB formation has been considered to be a marker for neuronal degeneration because neuronal loss is found in the predilection sites for LBs. However, recent studies have indicated that nonfibrillar α-synuclein is cytotoxic and that fibrillar aggregates of α-synuclein (LBs and pale bodies) may represent a cytoprotective mechanism in PD. 相似文献
4.
Bogomazova A. N. Eremeev A. V. Pozmogova G. E. Lagarkova M. A. 《Molecular Biology》2019,53(6):838-849
Molecular Biology - Polyglutamine diseases are rare, inherited neurodegenerative pathologies that arise as a result of expansion of trinucleotide CAG repeats in the coding segment of certain genes.... 相似文献
5.
The substantia nigra plays important roles in the brain function and is critical in the development of many diseases, particularly Parkinson??s disease. Pathological changes of the substantia nigra have also been reported in other neurodegenerative diseases. Using a quantitative proteomic approach, we investigated protein expressions in the substantia nigra of Alzheimer??s disease, Huntington??s disease, and Multiple sclerosis. The expression level of one hundred and four proteins that were identified in at least three samples of each group were compared with the control group, with nineteen, twenty-two and thirteen proteins differentially expressed in Alzheimer??s diseases, Huntington??s disease and Multiple sclerosis respectively. The result indicates that the substantia nigra also undergoes functional adaption or damage in these diseases. 相似文献
6.
Bartzokis G Lu PH Tishler TA Fong SM Oluwadara B Finn JP Huang D Bordelon Y Mintz J Perlman S 《Neurochemical research》2007,32(10):1655-1664
Background
Postmortem and in vivo imaging data support the hypothesis that premature myelin breakdown and subsequent homeostatic remyelination
attempts with increased oligodendrocyte and iron levels may contribute to Huntington’s Disease (HD) pathogenesis and the symmetrical
progress of neuronal loss from earlier-myelinating striatum to later-myelinating regions. A unique combination of in vivo
tissue integrity and iron level assessments was used to examine the hypothesis.
Methods A method that uses two Magnetic resonance imaging (MRI) instruments operating at different field-strengths was used to quantify
the iron content of ferritin molecules (ferritin iron) as well as tissue integrity in eight regions in 11 HD and a matched
group of 27 healthy control subjects. Three white matter regions were selected based on their myelination pattern (early to
later-myelinating) and fiber composition. These were frontal lobe white matter (Fwm) and splenium and genu of the corpus callosum
(Swm and Gwm). In addition, gray matter structures were also chosen based on their myelination pattern and fiber composition.
Three striatum structures were assessed [caudate, putamen, and globus pallidus (C, P, and G)] as well as two comparison gray
matter regions that myelinate later in development and are relatively spared in HD [Hippocampus (Hipp) and Thalamus (Th)].
Results Compared to healthy controls, HD ferritin iron levels were significantly increased in striatum C, P, and G, decreased in Fwm
and Gwm, and were unchanged in Hipp, Th, and Swm. Loss of tissue integrity was observed in C, P, Fwm, and especially Swm but
not Hipp, Th, G, or Gwm. This pattern of findings was largely preserved when a small subset of HD subjects early in the disease
process was examined.
Conclusions The data suggest early in the HD process, myelin breakdown and changes in ferritin iron distribution underlie the pattern
of regional toxicity observed in HD. Prospective studies are needed to verify myelin breakdown and increased iron levels are
causal factors in HD pathogenesis. Tracking the effects of novel interventions that reduce myelin breakdown and iron accumulation
in preclinical stages of HD could hasten the development of preventive treatments.
Special issue dedicated to Dr. Moussa Youdim. 相似文献
7.
Jianfang Chen Eileen Marks Barry Lai Zhaojie Zhang James A. Duce Linh Q. Lam Irene Volitakis Ashley I. Bush Steven Hersch Jonathan H. Fox 《PloS one》2013,8(10)
Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine-encoding CAG expansion in the huntingtin gene. Iron accumulates in the brains of HD patients and mouse disease models. However, the cellular and subcellular sites of iron accumulation, as well as significance to disease progression are not well understood. We used independent approaches to investigate the location of brain iron accumulation. In R6/2 HD mouse brain, synchotron x-ray fluorescence analysis revealed iron accumulation as discrete puncta in the perinuclear cytoplasm of striatal neurons. Further, perfusion Turnbull’s staining for ferrous iron (II) combined with transmission electron microscope ultra-structural analysis revealed increased staining in membrane bound peri-nuclear vesicles in R6/2 HD striatal neurons. Analysis of iron homeostatic proteins in R6/2 HD mice revealed decreased levels of the iron response proteins (IRPs 1 and 2) and accordingly decreased expression of iron uptake transferrin receptor (TfR) and increased levels of neuronal iron export protein ferroportin (FPN). Finally, we show that intra-ventricular delivery of the iron chelator deferoxamine results in an improvement of the motor phenotype in R6/2 HD mice. Our data supports accumulation of redox-active ferrous iron in the endocytic / lysosomal compartment in mouse HD neurons. Expression changes of IRPs, TfR and FPN are consistent with a compensatory response to an increased intra-neuronal labile iron pool leading to increased susceptibility to iron-associated oxidative stress. These findings, together with protection by deferoxamine, support a potentiating role of neuronal iron accumulation in HD. 相似文献
8.
9.
10.
Trust and Memory: Organizational Strategies, Institutional Conditions and Trust Negotiations in Specialty Clinics for Alzheimer’s Disease 总被引:1,自引:0,他引:1
Beard RL 《Culture, medicine and psychiatry》2008,32(1):11-30
Clinicians aim to establish trust during medical encounters because, without it, health consumers may not seek medical care,
consider their diagnoses legitimate, or adhere to treatment regimens. This paper examines the identification and treatment
of memory loss within two specialty clinics to understand how cultural dynamics, such as organizational ethos and work practices,
influence the social fabric of cognitive evaluations. Ethnographic data suggest important historical and cultural differences
in the approaches to Alzheimer’s disease (AD). Organizational routines, however, support a common goal, that of moving individuals
from “potential patients” to patients, and ultimately research subjects, through establishing trust. Although the processes
through which trust is potentially achieved, or the social conditions of trust, were similar at the sites, the object of trust was different. Whereas one clinic encouraged trust in collective medical
expertise, the other focused on trust in specific clinicians. These conditions affect the clinical consequences of trust, particularly how and when the diagnosis is delivered, use of the AD label and other terminology, and the level
of standardization. The individual
consequences include perceptions of patients and depictions of the prognosis. Whether cognitive impairment is viewed as a scientific puzzle
to be solved or is seen as a chronic illness significantly shapes the organizational processes of clinical evaluation. Alzheimer’s
disease, as a cultural object, is a particularly salient exemplar of the clinical negotiation of ambiguous diagnostic categorizations
and the unpredictable patient in daily biomedical practice.
相似文献
Renée L. BeardEmail: |
11.
Catherine Schramm Sandrine Katsahian Katia Youssov Jean-Fran?ois Démonet Pierre Krystkowiak Frédéric Supiot Christophe Verny Laurent Cleret de Langavant Anne-Catherine Bachoud-Lévi European Huntington's Disease Initiative Study Group the Multicentre Intracerebral Grafting in Huntington's Disease Group 《PloS one》2015,10(12)
The retest effect—improvement of performance on second exposure to a task—may impede the detection of cognitive decline in clinical trials for neurodegenerative diseases. We assessed the impact of the retest effect in Huntington’s disease trials, and investigated its possible neutralization. We enrolled 54 patients in the Multicentric Intracerebral Grafting in Huntington’s Disease (MIG-HD) trial and 39 in the placebo arm of the Riluzole trial in Huntington’s Disease (RIL-HD). All were assessed with the Unified Huntington’s Disease Rating Scale (UHDRS) plus additional cognitive tasks at baseline (A1), shortly after baseline (A2) and one year later (A3). We used paired t-tests to analyze the retest effect between A1 and A2. For each task of the MIG-HD study, we used a stepwise algorithm to design models predictive of patient performance at A3, which we applied to the RIL-HD trial for external validation. We observed a retest effect in most cognitive tasks. A decline in performance at one year was detected in 3 of the 15 cognitive tasks with A1 as the baseline, and 9 of the 15 cognitive tasks with A2 as the baseline. We also included the retest effect in performance modeling and showed that it facilitated performance prediction one year later for 14 of the 15 cognitive tasks. The retest effect may mask cognitive decline in patients with neurodegenerative diseases. The dual baseline can improve clinical trial design, and better prediction should homogenize patient groups, resulting in smaller numbers of participants being required. 相似文献
12.
Lauren M. Turner Rodney J. Croft Andrew Churchyard Jeffrey C. L. Looi Deborah Apthorp Nellie Georgiou-Karistianis 《PloS one》2015,10(9)
Background
Huntington''s disease (HD) causes progressive motor dysfunction through characteristic atrophy. Changes to neural structure begin in premanifest stages yet individuals are able to maintain a high degree of function, suggesting involvement of supportive processing during motor performance. Electroencephalography (EEG) enables the investigation of subtle impairments at the neuronal level, and possible compensatory strategies, by examining differential activation patterns. We aimed to use EEG to investigate neural motor processing (via the Readiness Potential; RP), premotor processing and sensorimotor integration (Contingent Negative Variation; CNV) during simple motor performance in HD.Methods
We assessed neural activity associated with motor preparation and processing in 20 premanifest (pre-HD), 14 symptomatic HD (symp-HD), and 17 healthy controls. Participants performed sequential tapping within two experimental paradigms (simple tapping; Go/No-Go). RP and CNV potentials were calculated separately for each group.Results
Motor components and behavioural measures did not distinguish pre-HD from controls. Compared to controls and pre-HD, symp-HD demonstrated significantly reduced relative amplitude and latency of the RP, whereas controls and pre-HD did not differ. However, early CNV was found to significantly differ between control and pre-HD groups, due to enhanced early CNV in pre-HD.Conclusions
For the first time, we provide evidence of atypical activation during preparatory processing in pre-HD. The increased activation during this early stage of the disease may reflect ancillary processing in the form of recruitment of additional neural resources for adequate motor preparation, despite atrophic disruption to structure and circuitry. We propose an early adaptive compensation mechanism in pre-HD during motor preparation. 相似文献13.
Xuan Zhang Erik R. Abels Jasmina S. Redzic Julia Margulis Steve Finkbeiner Xandra O. Breakefield 《Cellular and molecular neurobiology》2016,36(3):459-470
In Huntington’s disease (HD) the imperfect expanded CAG repeat in the first exon of the HTT gene leads to the generation of a polyglutamine (polyQ) protein, which has some neuronal toxicity, potentially mollified by formation of aggregates. Accumulated research, reviewed here, implicates both the polyQ protein and the expanded repeat RNA in causing toxicity leading to neurodegeneration in HD. Different theories have emerged as to how the neurodegeneration spreads throughout the brain, with one possibility being the transport of toxic protein and RNA in extracellular vesicles (EVs). Most cell types in the brain release EVs and these have been shown to contain neurodegenerative proteins in the case of prion protein and amyloid-beta peptide. In this study, we used a model culture system with an overexpression of HTT-exon 1 polyQ-GFP constructs in human 293T cells and found that the EVs did incorporate both the polyQ-GFP protein and expanded repeat RNA. Striatal mouse neural cells were able to take up these EVs with a consequent increase in the green fluorescent protein (GFP) and polyQ-GFP RNAs, but with no evidence of uptake of polyQ-GFP protein or any apparent toxicity, at least over a relatively short period of exposure. A differentiated striatal cell line expressing endogenous levels of Hdh mRNA containing the expanded repeat incorporated more of this mRNA into EVs as compared to similar cells expressing this mRNA with a normal repeat length. These findings support the potential of EVs to deliver toxic expanded trinucleotide repeat RNAs from one cell to another, but further work will be needed to evaluate potential EV and cell-type specificity of transfer and effects of long-term exposure. It seems likely that expanded HD-associated repeat RNA may appear in biofluids and may have use as biomarkers of disease state and response to therapy. 相似文献
14.
Mario Quarantelli Elena Salvatore Sara Maria Delle Acque Giorgio Alessandro Filla Amedeo Cervo Cinzia Valeria Russo Sirio Cocozza Marco Massarelli Arturo Brunetti Giuseppe De Michele 《PloS one》2013,8(8)
Previous MRI studies of functional connectivity in pre-symptomatic mutation carriers of Huntington’s disease (HD) have shown dysfunction of the Default-Mode Network (DMN). No data however are currently available on the DMN alterations in the symptomatic stages of the disease, which are characterized by cortical atrophy involving several DMN nodes. We assessed DMN integrity and its possible correlations with motor and cognitive symptoms in 26 symptomatic HD patients as compared to 22 normal volunteers, by analyzing resting state functional MRI data, using the Precuneal Cortex/Posterior Cingulate Cortices (PC/PCC) as seed, controlling at voxel level for the effect of atrophy by co-varying for gray matter volume. Direct correlation with PC/PCC was decreased, without correlation with atrophy, in the ventral medial prefrontal cortex (including anterior cingulate and subgenual cortex), right dorso-medial prefrontal cortex, and in the right inferior parietal cortex (mainly involving the angular gyrus). Negative correlations with PC/PCC were decreased bilaterally in the inferior parietal cortices, while a cluster in the right middle occipital gyrus presented increased correlation with PC/PCC. DMN changes in the ventral medial prefrontal cortex significantly correlated with the performance at the Stroop test (p = .0002). Widespread DMN changes, not correlating with the atrophy of the involved nodes, are present in symptomatic HD patients, and correlate with cognitive disturbances. 相似文献
15.
Brijesh Kumar Singh Naman Vatsa Vinod K. Nelson Vipendra Kumar Shashi Shekhar Kumar Subhash C. Mandal Mahadeb Pal Nihar Ranjan Jana 《Molecular neurobiology》2018,55(8):6337-6346
Huntington’s disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by expansion of CAG repeats in the coding area of huntingtin gene. In the HD brain, mutant huntingtin protein goes through proteolysis, and its amino-terminal portion consisting of polyglutamine repeats accumulate as inclusions that result in progressive impairment of cellular protein quality control system. Here, we demonstrate that partial rescue of the defective protein quality control in HD model mouse by azadiradione (a bioactive limonoids found in the seed of Azadirachta indica) could potentially improve the disease pathology. Prolonged treatment of azadiradione to HD mice significantly improved the progressive deterioration in body weight, motor functioning along with extension of lifespan. Azadiradione-treated HD mice brain also exhibited considerable decrease in mutant huntingtin aggregates load and improvement of striatal pathology in comparison with age-matched saline-treated HD controls. Biochemical analysis further revealed upregulation and activation of not only HSF1 (master regulator of protein folding) but also Ube3a (an ubiquitin ligase involved in the clearance of mutant huntingtin) in azadiradione-treated mice. Our results indicate that azadiradione-mediated enhanced folding and clearance of mutant huntingtin might underlie improved disease pathology in HD mice and suggests that it could be a potential therapeutic molecule to delay the progression of HD. 相似文献
16.
Jeon GS Kim KY Hwang YJ Jung MK An S Ouchi M Ouchi T Kowall N Lee J Ryu H 《Molecular neurobiology》2012,45(3):550-563
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder of mid-life onset characterized by involuntary movements and progressive cognitive decline caused by a CAG repeat expansion in exon 1 of the Huntingtin (Htt) gene. Neuronal DNA damage is one of the major features of neurodegeneration in HD, but it is not known how it arises or relates to the triplet repeat expansion mutation in the Htt gene. Herein, we found that imbalanced levels of non-phosphorylated and phosphorylated BRCA1 contribute to the DNA damage response in HD. Notably, nuclear foci of γ-H2AX, the molecular component that recruits various DNA damage repair factors to damage sites including BRCA1, were deregulated when DNA was damaged in HD cell lines. BRCA1 specifically interacted with γ-H2AX via the BRCT domain, and this association was reduced in HD. BRCA1 overexpression restored γ-H2AX level in the nucleus of HD cells, while BRCA1 knockdown reduced the spatiotemporal propagation of γ-H2AX foci to the nucleoplasm. The deregulation of BRCA1 correlated with an abnormal nuclear distribution of γ-H2AX in striatal neurons of HD transgenic (R6/2) mice and BRCA1(+/-) mice. Our data indicate that BRCA1 is required for the efficient focal recruitment of γ-H2AX to the sites of neuronal DNA damage. Taken together, our results show that BRCA1 directly modulates the spatiotemporal dynamics of γ-H2AX upon genotoxic stress and serves as a molecular maker for neuronal DNA damage response in HD. 相似文献
17.
Bezprozvanny I 《Neurochemical research》2011,36(7):1186-1197
Huntington’s disease (HD) and spinocerebellar ataxias (SCAs) are autosomal-dominant neurodegenerative disorders. HD is caused
by polyglutamine (polyQ) expansion in the amino-terminal region of a protein huntingtin (Htt) and primarily affects medium
spiny striatal neurons (MSN). Many SCAs are caused by polyQ-expansion in ataxin proteins and primarily affect cerebellar Purkinje
cells. The reasons for neuronal dysfunction and death in HD and SCAs remain poorly understood and no cure is available for
the patients. Our laboratory discovered that mutant huntingtin, ataxin-2 and ataxin-3 proteins specifically bind to the carboxy-terminal
region of the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1), an intracellular Ca2+ release channel. Moreover, we found that association of mutant huntingtin or ataxins with IP3R1 causes sensitization of IP3R1 to activation by IP3 in planar lipid bilayers and in neuronal cells. These results suggested that deranged neuronal Ca2+ signaling might play an important role in pathogenesis of HD, SCA2 and SCA3. In support of this idea, we demonstrated a connection
between abnormal Ca2+ signaling and neuronal cell death in experiments with HD, SCA2 and SCA3 transgenic mouse models. Additional data in the literature
indicate that abnormal neuronal Ca2+ signaling may also play an important role in pathogenesis of SCAl, SCA5, SCA6, SCA14 and SCA15/16. Based on these results
I propose that IP3R and other Ca2+ signaling proteins should be considered as potential therapeutic targets for treatment of HD and SCAs. 相似文献
18.
19.
Aging is associated with an enhanced susceptibility to brain dysfunction, loss of memory, and cognitive decline and significantly
influences the quality of life for the affected individual. Recent molecular–genetic approaches have provided powerful insights
into common age-related diseases that are both progressive and multifactorial, such as Alzheimer’s disease (AD), and in vitro
in AD models. These investigations have uncovered consistent deficits in brain gene signaling mechanisms and neurotrophic
substances known to contribute to normal brain function. Inflammatory signaling pathways involving up-regulation of cytosolic
phospholipase A2 and the arachidonic acid cycle, the depletion of the brain-essential fatty acid docosahexaenoic acid (DHA) and DHA-derived
neuroprotectin D1, and changes in the expression of key proapoptotic and antiapoptotic members of the Bcl-2 gene family are
thought to be major contributors to pathogenic processes in degenerating brain tissue. This review will focus on the roles
of stress genes, apoptosis-related genes, and inflammation in the molecular genetics of AD with emphasis on the interactive
nature of inflammatory, neurotrophic, and apoptotic signaling and will highlight areas of rapid progress in the characterization
of action of DHA and neuroprotectin D1 and address important research challenges. We also attempt to integrate these molecular,
genetic, and neurochemical changes with cellular pathways involved in brain aging to formulate an integrated understanding
of multifactorial age-related neurologic disease and pharmacotherapeutic strategies that may be useful in the restoration
of homeostatic brain function. 相似文献
20.
Genetic variation in clusterin gene, also known as apolipoprotein J, has been associated with Alzheimer’s disease (AD) through
replicated genome-wide studies, and plasma clusterin levels are associated with brain atrophy, baseline prevalence and severity,
and rapid clinical progression in patients with AD, highlighting the importance of clusterin in AD pathogenesis. Emerging
data suggest that clusterin contributes to AD through various pathways, including amyloid-β aggregation and clearance, lipid
metabolism, neuroinflammation, and neuronal cell cycle control and apoptosis. Moreover, epigenetic regulation of the clusterin
expression also seems to play an important role in the pathogenesis of AD. Emerging knowledge of the contribution of clusterin
to the pathogenesis of AD presents new opportunities for AD therapy. 相似文献