Familial Neurodegenerative Disorders Research Articles

Zebrafish Models of Rare Neurological Diseases like Spinocerebellar Ataxias (SCAs): Advantages and Limitations.

Spinocerebellar ataxia (SCA) is a heterogeneous group of rare familial neurodegenerative disorders that share the key feature of cerebellar ataxia. Clinical heterogeneity, diverse gene mutations and complex neuropathology pose significant challenges for developing effective disease-modifying therapies in SCAs. Without a deep understanding of the molecular mechanisms involved for each SCA, we cannot succeed in developing targeted therapies. Animal models are our best tool to address these issues and several have been generated to study the pathological conditions of SCAs. Among them, zebrafish (Danio rerio) models are emerging as a powerful tool for in vivo study of SCAs, as well as rapid drug screens. In this review, we will summarize recent progress in using zebrafish to study the pathology of SCAs. We will discuss recent advancements on how zebrafish models can further clarify underlying genetic, neuroanatomical, and behavioral pathogenic mechanisms of disease. We highlight their usefulness in rapid drug discovery and large screens. Finally, we will discuss the advantages and limitations of this in vivo model to develop tailored therapeutic strategies for SCA.

Huntington's Disease Pathogenesis: Two Sequential Components.

Historically, Huntington’s disease (HD; OMIM #143100) has played an important role in the enormous advances in human genetics seen over the past four decades. This familial neurodegenerative disorder involves variable onset followed by consistent worsening of characteristic abnormal movements along with cognitive decline and psychiatric disturbances. HD was the first autosomal disease for which the genetic defect was assigned to a position on the human chromosomes using only genetic linkage analysis with common DNA polymorphisms. This discovery set off a multitude of similar studies in other diseases, while the HD gene, later renamed HTT, and its vicinity in chromosome 4p16.3 then acted as a proving ground for development of technologies to clone and sequence genes based upon their genomic location, with the growing momentum of such advances fueling the Human Genome Project. The identification of the HD gene has not yet led to an effective treatment, but continued human genetic analysis of genotype-phenotype relationships in large HD subject populations, first at the HTT locus and subsequently genome-wide, has provided insights into pathogenesis that divide the course of the disease into two sequential, mechanistically distinct components.

The role of mutations associated with familial neurodegenerative disorders on blood\u2013brain barrier function in an iPSC model

BackgroundBlood–brain barrier dysfunction is associated with many late-stage neurodegenerative diseases. An emerging question is whether the mutations associated with neurodegenerative diseases can independently lead to blood–brain barrier (BBB) dysfunction. Studies from patient-derived induced pluripotent stem cells suggest that mutations associated with neurodegenerative disease are non-cell autonomous, resulting in gain of toxic function in derived neurons and astrocytes. Here we assess whether selected mutations associated with neurodegenerative diseases can contribute to impairment of the blood–brain barrier.MethodsWe assessed barrier function of confluent monolayers of human brain microvascular endothelial cells (hBMECs) derived from induced pluripotent stem cells (iPSC) from three healthy individuals and eight individuals with neurodegenerative disease. We systematically assessed protein and gene expression of BBB biomarkers, transendothelial resistance (TEER), permeability of Lucifer yellow, permeability of d-glucose, permeability of rhodamine 123, the efflux ratio of rhodamine 123, and P-gp inhibition using Tariquidar for confluent monolayers of human brain microvascular endothelial cell (hBMECs).ResultsWe provide evidence supporting the hypothesis that mutations associated with neurodegenerative disease can independently cause BBB dysfunction. These functional changes are not catastrophic since barrier breakdown would result in BBB impairment during development. Synergistic interactions between non-cell autonomous cerebrovascular dysfunction and the effects of gain-of-toxic function in neurons (e.g. toxic oligomers) are likely to increase disease burden through a positive feedback mechanism.ConclusionsThese results suggest that the accumulation of defects in brain microvascular endothelial cells may ultimately lead to impairment of the BBB. Small changes in barrier function over time could lead to accumulated defects that result in positive feedback to unrelated central nervous system diseases.

Autophagy and Human Neurodegenerative Diseases-A Fly's Perspective.

Neurodegenerative diseases in humans are frequently associated with prominent accumulation of toxic protein inclusions and defective organelles. Autophagy is a process of bulk lysosomal degradation that eliminates these harmful substances and maintains the subcellular environmental quality. In support of autophagy’s importance in neuronal homeostasis, several genetic mutations that interfere with autophagic processes were found to be associated with familial neurodegenerative disorders. In addition, genetic mutations in autophagy-regulating genes provoked neurodegenerative phenotypes in animal models. The Drosophila model significantly contributed to these recent developments, which led to the theory that autophagy dysregulation is one of the major underlying causes of human neurodegenerative disorders. In the current review, we discuss how studies using Drosophila enhanced our understanding of the relationship between autophagy and neurodegenerative processes.

Calcium dysregulation contributes to neurodegeneration in FTLD patient iPSC-derived neurons.

Mutations in the gene MAPT encoding tau, a microtubules-associated protein, cause a subtype of familial neurodegenerative disorder, known as frontotemporal lobar degeneration tauopathy (FTLD-Tau), which presents with dementia and is characterized by atrophy in the frontal and temporal lobes of the brain. Although induced pluripotent stem cell (iPSC) technology has facilitated the investigation of phenotypes of FTLD-Tau patient neuronal cells in vitro, it remains unclear how FTLD-Tau patient neurons degenerate. Here, we established neuronal models of FTLD-Tau by Neurogenin2-induced direct neuronal differentiation from FTLD-Tau patient iPSCs. We found that FTLD-Tau neurons, either with an intronic MAPT mutation or with an exonic mutation, developed accumulation and extracellular release of misfolded tau followed by neuronal death, which we confirmed by correction of the intronic mutation with CRISPR/Cas9. FTLD-Tau neurons showed dysregulation of the augmentation of Ca2+ transients evoked by electrical stimulation. Chemogenetic or pharmacological control of neuronal activity-relevant Ca2+ influx by the introduction of designer receptors exclusively activated by designer drugs (DREADDs) or by the treatment with glutamate receptor blockers attenuated misfolded tau accumulation and neuronal death. These data suggest that neuronal activity may regulate neurodegeneration in tauopathy. This FTLD-Tau model provides mechanistic insights into tauopathy pathogenesis and potential avenues for treatments.

Multiparametric 3T MRI evaluation of hereditary spastic paraplegia: A case report.

Hereditary spastic paraplegia (HSP) is a rare heterogeneous group of familial neurodegenerative disorders characterized by degeneration of the corticospinal tracts and posterior column of the spinal cord. Previously described radiological findings included nonspecific brain abnormalities such as brain atrophy and white matter lesions, as well as atrophy of the corpus callosum and spinal cord. Magnetic resonance spectroscopy may reveal reduced concentrations of normal brain metabolites and elevated levels of myoinositol. Diffusion tensor imaging shows increased mean diffusivity and reduced fractional anisotropy in the periventricular white matter, which is compatible with damaged myelinated axons. We present here two cases of HSP in a single family with typical imaging findings.

MutSβ promotes trinucleotide repeat expansion by recruiting DNA polymerase β to nascent (CAG)n or (CTG)n hairpins for error-prone DNA synthesis.

Expansion of (CAG)•(CTG) repeats causes a number of familial neurodegenerative disorders. Although the underlying mechanism remains largely unknown, components involved in DNA mismatch repair, particularly mismatch recognition protein MutSβ (a MSH2-MSH3 heterodimer), are implicated in (CAG)•(CTG) repeat expansion. In addition to recognizing small insertion-deletion loop-outs, MutSβ also specifically binds DNA hairpin imperfect heteroduplexes formed within (CAG)n•(CTG)n sequences. However, whether or not and how MutSβ binding triggers expansion of (CAG)•(CTG) repeats remain unknown. We show here that purified recombinant MutSβ physically interacts with DNA polymerase β (Polβ) and stimulates Polβ-catalyzed (CAG)n or (CTG)n hairpin retention. Consistent with these in vitro observations, MutSβ and Polβ interact with each other in vivo, and colocalize at (CAG)•(CTG) repeats during DNA replication. Our data support a model for error-prone processing of (CAG)n or (CTG)n hairpins by MutSβ and Polβ during DNA replication and/or repair: MutSβ recognizes (CAG)n or (CTG)n hairpins formed in the nascent DNA strand, and recruits Polβ to the complex, which then utilizes the hairpin as a primer for extension, leading to (CAG)•(CTG) repeat expansion. This study provides a novel mechanism for trinucleotide repeat expansion in both dividing and non-dividing cells.

The Role of Cathepsin D in the Pathogenesis of Human Neurodegenerative Disorders.

In familial neurodegenerative disorders, protein aggregates form continuously because of genetic mutations that drive the synthesis of truncated or unfolded proteins. The oxidative stress imposed by neurotransmitters and environmental neurotoxins constitutes an additional threat to the folding of the proteins and the integrity of organelle membranes in neurons. Failure in degrading such altered materials compromises the function of neurons and eventually leads to neurodegeneration. The lysosomal proteolytic enzyme Cathepsin D is the only aspartic-type protease ubiquitously expressed in all the cells of the human body, and it is expressed at high level in the brain. In general, cathepsin D mediated proteolysis is essential to neuronal cell homeostasis through the degradation of unfolded or oxidized protein aggregates delivered to lysosomes via autophagy or endocytosis. More specifically, many altered neuronal proteins that hallmark neurodegenerative diseases (e.g., the amyloid precursor, α-synuclein, and huntingtin) are physiologic substrates of cathepsin D and would abnormally accumulate if not efficiently degraded by this enzyme. Furthermore, experimental evidence indicates that cathepsin D activity is linked to the metabolism of cholesterol and of glycosaminoglycans, which accounts for its involvement in neuronal plasticity. This review focuses on the unique role of cathepsin D mediated proteolysis in the pathogenesis of human neurodegenerative diseases.

Familial early-onset dementia with complex neuropathologic phenotype and genomic background

Despite significant progress in our understanding of hereditary neurodegenerative diseases, the list of genes associated with early-onset dementia is not yet complete. In the present study, we describe a familial neurodegenerative disorder characterized clinically as the behavioral and/or dysexecutive variant of Alzheimer’s disease with neuroradiologic features of Alzheimer’s disease, however, lacking amyloid-β deposits in the brain. Instead, we observed a complex, 4 repeat predominant, tauopathy, together with a TAR DNA-binding protein of 43 kDa proteinopathy. Whole-exome sequencing on 2 affected siblings and 1 unaffected aunt uncovered a large number of candidate genes, including LRRK2 and SYNE2. In addition, DDI1, KRBA1, and TOR1A genes possessed novel stop-gain mutations only in the patients. Pathway, gene ontology, and network interaction analysis indicated the involvement of pathways related to neurodegeneration but revealed novel aspects also. This condition does not fit into any well-characterized category of neurodegenerative disorders. Exome sequencing did not disclose a single disease-specific gene mutation suggesting that a set of genes working together in different pathways may contribute to the etiology of the complex phenotype.

Implication of Epigenetic Modifications in Neurodegenerative Disorders: Traces and Imprints

Neurodegenerative disorders like Alzheimer’s, Parkinson’s, Huntington’s and ALS; present a complex biological disorder resulting loss of synaptic connections, neuronal damage and decay in old and elderly persons. Such a degrading process of neurons affects the central nervous system and results in loss of cognitive abilities, memory, sensory abilities and impairs the motor neuron functions. Thus, understanding the biology of neurodegenerative diseases has been crucial in ensuring healthy aged life. Although several cases of familial neurodegenerative disorders have been reported, yet the mechanism for sporadic neuronal degeneration remains largely unknown. Therefore, in this review we aim to understand the role of environmental triggers, i.e. epigenetics in affecting the normal functioning and coordination of host nervous system. A distinct signature mark of neurodegenerative disorders involves misfolding and structural aberration in native proteins leading to formation of intracellular fibrillary tangles, Lewy bodies, extracellular plaques, to name a few. This paper focusses primarily on four kinds of neurodegenerative disorders as mentioned above and reviewed the role of DNA/histone methylation, acetylation, ubiquitination along with mutational changes to the native protein product.

A2 TRACK-HD and TRACK-ON HD: yielding new insights in Huntington's disease

Professor Sarah Tabrizi is Professor of Clinical Neurology at UCL Institute of Neurology, and an Honorary Consultant Neurologist at the National Hospital for Neurology and Neurosurgery. After undergraduate degrees in Biochemistry and Medicine at the University of Edinburgh, Sarah undertook her PhD at UCL as an MRC Clinical Training Fellow studying the role of mitochondrial dysfunction in cellular neurodegeneration. After clinical training in Neurology, in 2002 she was awarded a 5-year MRC/DH National Clinician Scientist Fellowship, enabling her to establish her own research group, studying cellular mechanisms of neurodegeneration, concentrating on protein misfolding diseases, particularly prion disease and Huntington9s disease. In 2006, she was awarded one of the first HEFCE New Blood Senior Lectureships; in 2007 she was promoted to Reader and in 2009 to Professor at UCL. In addition to bench science which focuses on cellular mechanisms of neurodegeneration, Sarah also leads a large translational research programme in Huntington9s disease working towards finding treatments for this disease. Sarah is PI of TRACK-HD, a major international research initiative aimed at understanding the neurobiology of the neurodegenerative changes in premanifest and early stage HD gene carriers, which is essential for the development of disease-modifying therapies to treat this disorder. She also first described the role of the immune system as a modifier of Huntington9s disease pathogenesis, and has an ongoing research interest in this area. Professor Tabrizi has had funding from the MRC, Wellcome Trust, CHDI/High Q Foundation, EU Framework 7, UK HD association, Brain Research Trust, Dementia and Neurodegenerative Diseases Network (Dendron) and the UCL/UCLH BRC for her research. Huntington9s disease (HD) is a neurodegenerative condition characterised by deterioration of motor and cognitive function as well as neuropsychiatric disturbance. The mean age of onset is 40 years, and progression is slow and inexorable, with death occurring typically 15–20 years later. It is inherited in an autosomal dominant manner, causing devastation to affected families. Currently there are no treatments available which modify disease progression. However, novel therapeutic agents specifically targeting HD pathology are now on the horizon.¹ TRACK-HD is an ongoing, large multi-national observational study which aims to investigate a range of potential biomarkers in premanifest HD gene carriers and early HD subjects which may have utility in clinical trials. Standardised data collection of state-of-the-art 3 T MR imaging and novel cognitive, quantitative motor, oculomotor, and neuropsychiatric assessments across four international sites has been achieved, with minimal dropout of subjects over a 3-year period. Baseline analysis of 123 controls, 120 premanifest gene carriers and 123 early HD subjects identified measures which were able to detect disease effects several years prior to symptom onset.² Follow-up analysis found that imaging measures were the most sensitive to change at all stages of the disease from premanifest to early HD³; these techniques were able to identify subtle changes over just 1 year in this slowly progressive, heterogeneous condition and consequently show promise as potential biomarkers for future therapeutic trials. TRACK-HD is also undertaking genetic, biochemical and epigenetic profiling of all subjects to help identify key modifiers of the pathogenic disease process. Data from TRACK-HD has been presented at meetings of the European Medicines Agency and FDA (8th November 2010 Expert meeting in familial neurodegenerative disorders London) as an example of how international collaborative studies can set the benchmark towards identifying outcomes measures to test novel therapies in subjects many years before symptom onset, or with very early disease. TRACK-HD has advanced our understanding of both the clinical manifestation and underlying pathobiology of HD in the earliest phase of the neurodegenerative disease process, such that we are now better-equipped to enter disease-modifying clinical trials and offer hope to the families affected by this devastating disease. <h3>References</h3> 1. <b>Ross CA</b>, Tabrizi SJ. Huntington9s disease: from molecular pathogenesis to clinical treatment. <i>Lancet Neurol</i> 2011;<b>10:</b>83–98. 2. <b>Tabrizi SJ</b>, Langbehn DR, Leavitt BR, <i>et al.</i> Biological and clinical manifestations of Huntington9s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. <i>Lancet Neurol</i> 2009;<b>8</b>:791–801. 3. <b>Tabrizi SJ</b>, Scahill RI, Durr A, <i>et al.</i> Biological and clinical changes in premanifest and early stage Huntington9s disease in the TRACK-HD study: the 12-month longitudinal analysis. <i>Lancet Neurol</i> 2011;<b>10</b>:31–42.

Parkinsonism and Frontotemporal Dementia: The Clinical Overlap

Frontotemporal dementia is commonly associated with parkinsonism in several sporadic (i.e., progressive supranuclear palsy, corticobasal degeneration) and familial neurodegenerative disorders (i.e., frontotemporal dementia associated with parkinsonism and MAPT or progranulin mutations in chromosome 17). The clinical diagnosis of these disorders may be challenging in view of overlapping clinical features, particularly in speech, language, and behavior. The motor and cognitive phenotypes can be viewed within a spectrum of clinical, pathologic, and genetic disorders with no discrete clinicopathologic correlations but rather lying within a dementia-parkinsonism continuum. Neuroimaging and cerebrospinal fluid analysis can be helpful, but the poor specificity of clinical and imaging features has enormously challenged the development of biological markers that could differentiate these disorders premortem. This gap is critical to bridge in order to allow testing of novel biological therapies that may slow the progression of these proteinopathies.

Die Bedeutung des Coeruloplasmins für die Differenzialdiagnose neuropsychiatrischer Störungen

The blue copper protein ceruloplasmin has been of interest to psychiatrists for decades following Heilmeyer's observation of elevated serum copper levels in schizophrenic patients. Immunoturbidimetry, however, does not yield elevated serum ceruloplasmin concentrations in schizophrenia while ceruloplasmin-related oxidase activity appears to be elevated in patients with schizophrenia and reduced in patients with Alzheimer's disease. Low serum concentrations of immuno-turbidimetrically measured ceruloplasmin, and of oxidase activity, are typical of Wilson's disease, Menkes' disease, and aceruloplasminemia, three familial neurodegenerative disorders of pronounced variability, with regard to both genotype and phenotype. Especially patients with Wilson's disease may exhibit behavioural symptoms only over a long period. Heterozygous carriers of Wilson's disease and aceruloplasminaemia may have low serum ceruloplasmin concentrations; they will not develop somatic symptoms, but the significance of these carrier states, or of "hypoceruloplasminaemia", with regard to mental disorders is unknown.

PET of Brain Prion Protein Amyloid in Gerstmann–Sträussler–Scheinker Disease

In vivo amyloid PET imaging was carried out on six symptomatic and asymptomatic carriers of PRNP mutations associated with the Gerstmann-Sträussler-Scheinker (GSS) disease, a rare familial neurodegenerative brain disorder demonstrating prion amyloid neuropathology, using 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([F-18]FDDNP). 2-Deoxy-2-[F-18]fluoro-d-glucose PET ([F-18]FDG) and magnetic resonance imaging (MRI) scans were also performed in each subject. Increased [F-18]FDDNP binding was detectable in cerebellum, neocortex and subcortical areas of all symptomatic gene carriers in close association with the experienced clinical symptoms. Parallel glucose metabolism ([F-18]FDG) reduction was observed in neocortex, basal ganglia and/or thalamus, which supports the close relationship between [F-18]FDDNP binding and neuronal dysfunction. Two asymptomatic gene carriers displayed no cortical [F-18]FDDNP binding, yet progressive [F-18]FDDNP retention in caudate nucleus and thalamus was seen at 1- and 2-year follow-up in the older asymptomatic subject. In vitro FDDNP labeling experiments on brain tissue specimens from deceased GSS subjects not participating in the in vivo studies indicated that in vivo accumulation of [F-18]FDDNP in subcortical structures, neocortices and cerebellum closely related to the distribution of prion protein pathology. These results demonstrate the feasibility of detecting prion protein accumulation in living patients with [F-18]FDDNP PET, and suggest an opportunity for its application to follow disease progression and monitor therapeutic interventions.

Alzheimer Disease–like Phenotype Associated With the c.154delA Mutation in Progranulin

To characterize a kindred with a familial neurodegenerative disorder associated with a mutation in progranulin (PGRN), with emphasis on the unique clinical features in this kindred. Antemortem and postmortem characterization of a kindred with a familial neurodegenerative disorder. Multispecialty group academic medical center. Affected members of a kindred with dementia with or without parkinsonism associated with a unique mutation in PGRN. Genotype-phenotype correlation. Of 10 affected individuals identified, 6 presented with early amnestic symptoms which resulted in initial diagnoses of Alzheimer disease or amnestic mild cognitive impairment. Some individuals presented with features characteristic of frontotemporal dementia. Mean age at onset was substantially younger in generation III (75.8 years; range, 69-80 years) than in generation II (60.7 years; range, 55-66 years). The pattern of cerebral atrophy varied widely in the affected individuals. Neuropathologic features in 6 individuals included frontotemporal lobar degeneration with ubiquitin-positive neuronal cytoplasmic and intranuclear inclusions (FTLD-U with NII). PGRN analysis revealed a single base pair deletion in exon 2 (c.154delA), which caused a frameshift (p.Thr52HisfsX2) and, therefore, creation of a premature termination codon and a likely null allele. In this large kindred, most affected individuals had clinical presentations that resembled Alzheimer disease or amnestic mild cognitive impairment associated with a mutation in PGRN and underlying FTLD-U with NII neuropathologic abnormalities. This finding is in distinct contrast to previously reported kindreds, in which clinical presentations have typically been within the spectrum of FTLD. The basis for the large difference in age at onset between generations requires further study.

Oxidative stress promotes mutant huntingtin aggregation and mutant huntingtin-dependent cell death by mimicking proteasomal malfunction

Huntington’s disease (HD) is a familial neurodegenerative disorder caused by an abnormal expansion of CAG repeats in the coding region of huntingtin gene. A major hallmark of HD is the proteolytic production of N-terminal fragments of huntingtin containing polyglutamine repeats that form ubiquitinated aggregates in the nucleus and cytoplasm of the affected neurons. However, the mechanism by which the mutant huntingtin causes neurodegeneration is not well understood. Here, we found that oxidative stimuli enhance the polyglutamine-expanded truncated N-terminal huntingtin (mutant huntingtin) aggregation and mutant huntingtin-induced cell death. Oxidative stimuli also lead to rapid proteasomal dysfunction in the mutant huntingtin expressing cells as compared to normal glutamine repeat expressing cells. Overexpression of Cu/Zn superoxide dismutase (SOD1), Hsp40 or Hsp70 reverses the oxidative stress-induced proteasomal malfunction, mutant huntingtin aggregation, and death of the mutant huntingtin expressing cells. Finally, we show the higher levels of expression of SOD1 and DJ-1 in the mutant huntingtin expressing cells. Our result suggests that oxidative stress-induced proteasomal malfunction might be linked with mutant huntingtin-induced cell death.

BRI2 Interacts with Amyloid Precursor Protein (APP) and Regulates Amyloid β (Aβ) Production

Transmembrane proteins BRI2 and amyloid precursor protein (APP) co-localize with amyloid β (Aβ) lesions in sporadic Alzheimer disease and mutations in both precursor proteins are linked to early-onset familial cases of cerebral amyloidosis associated with dementia and/or cerebral hemorrhage. A specific interaction between BRI2 and APP was unveiled by immunoprecipitation experiments using transfected and non-transfected cells. The use of deletion mutants further revealed that stretches 648–719 of APP751 and 46–106 of BRI2, both inclusive of the full transmembrane domains, are sufficient for the interaction. Removal of most of the APP and BRI2 extracellular domains without affecting the interaction implies that both proteins interact when are expressed on the same cell membrane (<i>cis</i>) rather than on adjacent cells (<i>trans</i>). The presence of BRI2 had a modulatory effect on APP processing, specifically increasing the levels of cellular APP as well as β-secretase-generated COOH-terminal fragments while decreasing the levels of α-secretase-generated COOH-terminal fragments as well as the secretion of total APP and Aβ peptides. Determining the precise molecular pathways affected by the specific binding between APP and BRI2 could result in the identification of common therapeutic targets for these sporadic and familial neurodegenerative disorders.

Microtubule-stabilising drugs for therapy of Alzheimer’s disease and other neurodegenerative disorders with axonal transport impairments

Increasing evidence implicates impairments of axonal transport in mechanisms underlying diverse neurodegenerative disease. This evidence includes discoveries of mutations in genes encoding human motor proteins or proteins involved in stabilising the microtubule (MT) network required for maintenance of axonal transport in familial neurodegenerative disorders, as well as data from in vivo and in vitro model systems. Moreover, in sporadic neurodegenerative disorders such as Alzheimer’s disease (AD), pathological alterations of the MT-binding protein tau are linked to impaired axonal transport and brain degeneration. Because MT-stabilising compounds hold promise for counteracting the loss of tau function in AD and sustaining effective axonal transport, we conclude that MT-binding/stabilising drugs show potential therapeutic utility for the treatment of AD and other neurodegenerative di-sorders characterised by altered MTs and impaired axonal transport.

Expression of the Small Heat-Shock Protein αB-Crystallin in Tauopathies with Glial Pathology

Intracellular accumulations of filamentous material composed of tau proteins are defining features of sporadic and familial neurodegenerative disorders termed "tauopathies." In Alzheimer's disease, the most common tauopathy, tau pathology is predominantly localized within neurons; however, robust glial pathology occurs in other tauopathies. Although the pathogenesis of tauopathies remains primarily unknown, molecular chaperones such as heat-shock proteins (HSPs) are implicated in these tau disorders as well as other neurodegenerative diseases characterized by the accumulation of insoluble protein aggregates such as alpha-synuclein in Parkinson's disease and polyglutamine in Huntington's disease. We analyzed a variety of tauopathies with antibodies to a panel of HSPs to determine their role in the pathogenesis of these disorders. Although HSPs are not found in neuronal tau inclusions, we demonstrate increased expression of the small HSP alphaB-crystallin in glial inclusions of both sporadic and familial tauopathies. alphaB-crystallin was observed in a subset of astrocytic and oligodendrocytic tau inclusions as well as the neuropil thread pathology in cellular processes, but the co-expression of alphaB-crystallin with tau inclusions was relatively specific to tauopathies with extensive glial pathology. Thus, increased alphaB-crystallin expression in glial tau inclusions may represent a response by glia to the accumulation of misfolded or aggregated tau protein that is linked to the pathogenesis of the glial pathology and distinct from mechanisms underlying neuronal tau pathology in neurodegenerative disease.

Recent advances in understanding the pathogenesis of polyglutamine diseases: involvement of molecular chaperones and ubiquitin-proteasome pathway

Polyglutamine diseases consist of a group of familial neurodegenerative disorders caused by expression of proteins containing expanded polyglutamine stretch. Over the past several years, tremendous progress has been made in identifying the molecular mechanisms by which the expanded polyglutamine tract leads to neuronal dysfunction and neurodegeneration. A common feature of most polyglutamine disorders is the occurrence of ubiquitin-positive neuronal intranuclear inclusions. The appearance of ubiquitinated aggregates implies an underline incapability of the cellular chaperones and proteasome machinery that normally functions to prevent the accumulation of misfolded proteins. Here we review the recent studies that have revealed a critical role for molecular chaperones and ubiquitin-proteasome pathway in the pathogenesis of polyglutamine diseases.