Extralysosomal Protein Degradation in Myofibrillar Myopathies

Myofibrillar myopathies (MFMs) are a group of heterogeneous muscle disorders morphologically defined by the presence of foci of dissolution of the myofibrils, accumulation of the products of myofibrillar degradation and ectopic expression of multiple proteins. MFMs represent the paradigm of conformational protein diseases of skeletal and cardiac muscles. Protein aggregation in MFMs is now considered to be the result of a failure of the extralysosomal proteolytic degradation system. Several factors including mutant proteins, aggresome formation and oxidative stress may compromise the ubiquitin–proteasome system, promoting the accumulation of potentially toxic protein aggregates within muscle cells.     

Aggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein

Expression of misfolded protein in cultured cells frequently leads to the formation of juxtanuclear inclusions that have been termed 'aggresomes'. Aggresome formation is an active cellular response that involves trafficking of the offending protein along microtubules, reorganization of intermediate filaments and recruitment of components of the ubiquitin proteasome system. Whether aggresomes are benevolent or noxious is unknown, but they are of particular interest because of the appearance of similar inclusions in protein deposition diseases. Here we present evidence that aggresomes serve a cytoprotective function and are associated with accelerated turnover of mutant proteins. We show that mutant androgen receptor (AR), the protein responsible for X-linked spinobulbar muscular atrophy, forms insoluble aggregates and is toxic to cultured cells. Mutant AR was also found to form aggresomes in a process distinct from aggregation. Molecular and pharmacological interventions were used to disrupt aggresome formation, revealing their cytoprotective function. Aggresome-forming proteins were found to have an accelerated rate of turnover, and this turnover was slowed by inhibition of aggresome formation. Finally, we show that aggresome-forming proteins become membrane-bound and associate with lysosomal structures. Together, these findings suggest that aggresomes are cytoprotective, serving as cytoplasmic recruitment centers to facilitate degradation of toxic proteins.     

Clusterin expression in follicular dendritic cells associated with prion protein accumulation

Peripheral accumulation of abnormal prion protein (PrP) in variant Creutzfeldt-Jakob disease and some animal models of transmissible spongiform encephalopathies (TSEs) may occur in the lymphoreticular system. Within the lymphoid tissues, abnormal PrP accumulation occurs on follicular dendritic cells (FDCs). Clusterin (apolipoprotein J) has been recognized as one of the molecules associated with PrP in TSEs, and clusterin expression is increased in the central nervous system where abnormal PrP deposition has occurred. We therefore examined peripheral clusterin expression in the context of PrP accumulation on FDCs in a range of human and experimental TSEs. PrP was detected immunohistochemically on tissue sections using a novel highly sensitive method involving detergent autoclaving pretreatment. A dendritic network pattern of clusterin immunoreactivity in lymphoid follicles was observed in association with the abnormal PrP on FDCs. The increased clusterin immunoreactivity appeared to correlate with the extent of PrP deposition, irrespective of the pathogen strains, host mouse strains or various immune modifications. The observed co-localization and correlative expression of these proteins suggested that clusterin might be directly associated with abnormal PrP. Indeed, clusterin immunoreactivity in association with PrP was retained after FDC depletion. Together these data suggest that clusterin may act as a chaperone-like molecule for PrP and play an important role in TSE pathogenesis.     

Inclusion Body Myositis: A Degenerative Muscle Disease Associated with Intra-Muscle Fiber Multi-Protein Aggregates, Proteasome Inhibition, Endoplasmic Reticulum Stress and Decreased Lysosomal Degradation

Sporadic inclusion body myositis (s-IBM), the most common muscle disease of older persons, is of unknown cause, and there is no enduring treatment. Abnormal accumulation of intracellular multi-protein inclusions is a characteristic feature of the s-IBM phenotype, and as such s-IBM can be considered a "conformational disorder," caused by protein unfolding/misfolding combined with the formation of inclusion bodies. Abnormal intracellular accumulation of unfolded proteins may lead to their aggregation and inclusion body formation.
The present article is focusing on the multiple proteins that are accumulated in the form of aggregates within s-IBM muscle fibers, and it explores the most recent research advances directed toward a better understanding of mechanisms causing their impaired degradation and abnormal aggregation. We illustrate that, among other factors, abnormal misfolding, accumulation and aggregation of proteins are associated with their inadequate disposal—and these factors are combined with, and perhaps provoked by, an aging intracellular milieu. Other concurrent and possibly provocative phenomena known within s-IBM muscle fibers are: endoplasmic reticulum stress and unfolded protein response, mitochondrial abnormalities, proteasome inhibition, lysosome abnormality and endodissolution. Together, these appear to lead to the s-IBM-specific vacuolar degeneration, and muscle fiber atrophy, concluding with muscle fiber death.     

The alternative role of 14-3-3 zeta as a sweeper of misfolded proteins in disease conditions

Here, we propose a novel hypothesis that 14-3-3 zeta might act as a sweeper of misfolded proteins by facilitating the formation of aggregates, which are referred to as inclusion bodies. Studies on the localization of the 14-3-3 proteins in different types of inclusion bodies in the brain including neurofibrillary tangle in Alzheimer's disease, pick bodies in Pick's disease, Lewy body-like hyaline inclusions in sporadic amyotrophic lateral sclerosis, prion/florid plaques in sporadic/variant Creutzfeldt-Jakob disease, nuclear inclusions in spinocerebellar ataxia-1, and possibly Lewy bodies in Parkinson's disease suggest a close association of these diseases with 14-3-3 zeta. The highly conserved hydrophobic surface of the amphipathic groove in 14-3-3 zeta represents a general mechanism with diverse cellular proteins, and it may also allow for the molecular recognition of misfolded proteins by hydrophobic interaction in disease conditions. When the abnormal processing of misfolded proteins overwhelms the quality control systems of the cell, it is likely that 14-3-3 zeta is recruited to form deposits of protein aggregates with nonnative, misfolded proteins in order to protect the cell against toxicity. Hence, 14-3-3 zeta may be considered as an auxiliary therapeutic tool in the protein aggregation disorders.     

Glucocorticoid modulation of androgen receptor nuclear aggregation and cellular toxicity is associated with distinct forms of soluble expanded polyglutamine protein.

Spinobulbar muscular atrophy is a progressive motor neuron disease caused by abnormal polyglutamine tract expansion in the androgen receptor (AR) gene, and is part of a family of central nervous system (CNS) neurodegenerative diseases, including Huntington's disease (HD). Each pathologic protein is widely expressed, but the cause of neuronal degeneration within the CNS remains unknown. Many reports now link abnormal polyglutamine protein aggregation to pathogenesis. A previous study reported that activation of the wild-type glucocorticoid receptor (wtGR) suppressed the aggregation of expanded polyglutamine proteins derived from AR and huntingtin, whereas a mutant receptor containing an internal deletion, GRDelta108-317, increased polyglutamine protein aggregation, in this case primarily within the nucleus. In this study, we use these two forms of GR to study expanded polyglutamine AR protein in different cell contexts. Using cell biology and biochemical approaches, we find that wtGR promotes soluble forms of the protein and prevents nuclear aggregation in NIH3T3 cells and cultured neurons. In contrast, GRDelta108-317 decreases polyglutamine protein solubility, and causes formation of nuclear aggregates in non-neuronal cells. Nuclear aggregates recruit hsp72 more rapidly than cytoplasmic aggregates, and are associated with decreased cell viability. Limited proteolysis and chemical cross-linking suggest unique soluble forms of the expanded AR protein underlie these distinct biological activities. These observations provide an experimental framework to understand why expanded polyglutamine proteins may be toxic only to certain populations of cells, and suggest that unique protein associations or conformations of expanded polyglutamine proteins may determine subsequent cellular effects such as nuclear localization and cellular toxicity.     

Interaction between Neuronal Intranuclear Inclusions and Promyelocytic Leukemia Protein Nuclear and Coiled Bodies in CAG Repeat Diseases

Neuronal intranuclear inclusions (NIIs) are a pathological hallmark of CAG repeat diseases. To elucidate the influence of NII formation on intranuclear substructures, we investigated the relationship of NIIs with nuclear bodies in brains of dentatorubral-pallidoluysian atrophy and Machado-Joseph disease. In both diseases, promyelocytic leukemia protein, a major component of the promyelocytic leukemia protein nuclear bodies, altered the normal distribution and was rearranged around NII, forming a single capsular structure. We further demonstrated that NIIs were present in close contact with coiled bodies, a highly dynamic domain that may be involved in the biogenesis of small nuclear ribonucleoproteins. The preferential association of intranuclear polyglutamine aggregates with coiled bodies was also confirmed in the dentatorubral-pallidoluysian atrophy transgenic mouse brain and culture cells expressing mutant atrophin-1. The results suggest that the interaction between NIIs and nuclear bodies may play a role in the pathogenesis of CAG repeat diseases.     

Beta adrenoceptor agonists, clenbuterol, and isoproterenol retard denervation atrophy in rat gastrocnemius muscle: use of 3-methylhistidine as a marker of myofibrillar degeneration

The effects of beta adrenergic agonists, clenbuterol (2 mg/kg body weight/d) and isoproterenol (12 mg/kg body weight/d), in normal innervated and denervated rat gastrocnemius muscle were investigated. The daily administration of beta adrenergic agonists to normal innervated rats for a short period (7 d) resulted in the hypertrophy of gastrocnemius as confirmed from the measurement of total tissue protein contents. The development of denervation atrophy witnessed a stimulation in the expression of acid and alkaline phosphatases, pointing to an enhanced myofibrillar degeneration. An administration of beta adrenergic agonists inhibited the expression of raised levels of these enzymes in denervated muscle. A measurement of 3-methylhistidine in muscle revealed a loss of amino acid with the progress in the development of denervation atrophy. Serum and urine samples from denervated rats showed a progressive accumulation of 3-methylhistidine. Clenbuterol and isoproterenol treatment to these rats resulted in an inhibition of 3-methylhistidine accumulation. When 3-methylhistidine was used as a marker of myofibrillar degeneration, the results seemed to suggest that the degeneration of cyto-contractile apparatus accompanying denervation atrophy is attenuated in the presence of beta adrenergic agonists, implying that these sympathomimetic drugs are capable of reversing denervation atrophy in rat gastrocnemius.     

The prion protein in human neuromuscular diseases

The basis of human prion diseases affecting the nervous system is accumulation of a disease-associated conformer (PrPSc) of the normal cellular prion protein (PrPC). Earlier studies demonstrated increased expression of PrPC in inclusion body myositis (IBM), dermato-, and polymyositis, as well as neurogenic muscle atrophy. To define the spectrum and reliability of PrPC immunoreactivity, its expression was examined systematically in a series of pathologically characterized muscular disorders by means of immunohistochemistry, confocal laser microscopy, and immunogold electron microscopy. Anti-PrPC immunolabelling of rimmed vacuoles was observed in IBM, inclusions of myofibrillary myopathy, targets, regenerating, and atrophic fibres, mononuclear cells, in addition to ragged red fibres in mitochondrial myopathies, and focal sarcolemmal immunostaining in non-diseased controls. Quantitative analysis demonstrated that, in neurogenic muscle lesions, anti-PrPC staining detects a significantly broader spectrum of fibres than anti-vimentin or anti-NCAM. In dystrophic muscle, PrPC expression was mainly restricted to regenerating fibres. In IBM, PrPC expression was not confined to rimmed vacuoles or vacuolated fibres and only a small percentage (7.1%) of rimmed vacuoles were PrPC positive. Ultrastructurally, PrPC was observed in the cytoplasm of lymphocytes, in the myofibrillar network of targets, and in rimmed vacuoles. Knowledge of disease circumstances with altered expression of PrPC is important in the setting of a potentially increased chance for extraneural PrPC-PrPSc conversion. In addition, our observations suggest that PrPC may have a general stress-response effect in various neuromuscular disorders.     

Dorfin localizes to the ubiquitylated inclusions in Parkinson's disease,dementia with Lewy bodies,multiple system atrophy,and amyotrophic lateral sclerosis

In many neurodegenerative diseases, the cytopathological hallmark is the presence of ubiquitylated inclusions consisting of insoluble protein aggregates. Lewy bodies in Parkinson's disease and dementia with Lewy bodies disease, glial cell inclusions in multiple system atrophy, and hyaline inclusions in amyotrophic lateral sclerosis (ALS) are representative of these inclusions. The elucidation of the components of these inclusions and the mechanisms underlying inclusion formation is important in uncovering the pathogenesis of these disorders. We hypothesized that Dorfin, a perinuclearly located E3 ubiquitin ligase, participates in the formation of ubiquitylated inclusions in a wide range of neurodegenerative diseases. Here, we report that affinity-purified anti-Dorfin antibody labeled ubiquitylated inclusions of Parkinson's disease, dementia with Lewy bodies disease, multiple system atrophy, and sporadic and familial ALS. A double-immunofluorescence study revealed that Dorfin shows a distribution pattern parallel to that of ubiquitin. Furthermore, by a filter trap assay, we detected that Dorfin is present in the ubiquitylated high-molecular weight structures derived from these diseases. These results suggest that Dorfin plays a crucial role in the formation of ubiquitylated inclusions of alpha-synucleinopathy and ALS. However, because we failed to show the direct binding of alpha-synuclein with Dorfin, future investigations into the binding partner(s) of Dorfin will be needed to deepen our understanding of the pathophysiology of alpha-synucleinopathy and ALS.     

Lafora disease proteins malin and laforin are recruited to aggresomes in response to proteasomal impairment

Lafora disease (LD), an autosomal recessive neurodegenerative disorder, is characterized by the presence of cytoplasmic polyglucosan inclusions known as Lafora bodies in several tissues including the brain. Laforin, a protein phosphatase, and malin, an ubiquitin ligase, are two of the proteins that are known to be defective in LD. Malin interacts with laforin and promotes its polyubiquitination and degradation. Here we show that malin and laforin co-localize in endoplasmic reticulum (ER) and that they form centrosomal aggregates when treated with proteasomal inhibitors in both neuronal and non-neuronal cells. Laforin/malin aggregates co-localize with gamma-tubulin and cause redistribution of alpha-tubulin. These aggregates are also immunoreactive to ubiquitin, ubiquitin-conjugating enzyme, ER chaperone and proteasome subunits, demonstrating their aggresome-like properties. Furthermore, we show that the centrosomal aggregation of laforin and malin is dependent on the functional microtubule network. Laforin and malin form aggresome when expressed together or otherwise, suggesting that the two proteins are recruited to the centrosome independent of each other. Taken together, our results suggest that the centrosomal accumulation of malin, possibly with the help of laforin, may enhance the ubiquitination of its substrates and facilitate their efficient degradation by proteasome. Defects in malin or laforin may thus lead to increased levels of misfolded and/or target proteins, which may eventually affect the physiological processes of the neuron. Thus, defects in protein degradation and clearance are likely to be the primary trigger in the physiopathology of LD.     

Transgenic Mice Over-Expressing the C-99 Fragment of βPP with an α-Secretase Site Mutation Develop a Myopathy Similar to Human Inclusion Body Myositis

Inclusion body myositis (IBM) is the most common muscle disease in the elderly. Amyloid-β protein (Aβ) has been shown to accumulate abnormally in the vacuolated fibers and to localize to amyloid-like fibrils in muscles from IBM patients. We studied the skeletal muscles from a line of transgenic mice over-expressing the carboxyl-terminal 99 amino acids (C99) of the β-amyloid precursor protein (βPP) with a substitution of lysine-612 to valine (K612V), intended to abolish α-secretase recognition and to preserve the Aβ domain of C99. The majority (87%) of the 24-month-old transgenic mice showed myopathic changes, and approximately one-third of them had degenerating fibers with sarcoplasmic vacuoles and thioflavin-S-positive deposits. Ultrastructurally, the inclusions were aggregates of short thin amyloid-like fibrils, 6 to 8 nm in diameter. These features are similar to those of human IBM. Immunocytochemistry using an antibody against Aβ showed membranous staining in most muscle fibers of transgenic mice, as well as granular or vacuolar cytoplasmic staining in the atrophic fibers. Western blots showed a high level of accumulation of carboxyl-terminal fragments of βPP in the muscles of the transgenic mice with the most severe IBM-like lesions. The expression of IBM-like lesions was age dependent. These transgenic mice provide a model for the study of IBM and for the peripheral expression of a key element in the pathogenesis of Alzheimer disease.     

Tubular up-regulation of clusterin mRNA in murine lupus-like nephritis.

Clusterin, a widely distributed glycoprotein, is detected in most tissues and in numerous physiological fluids. In the kidney, this protein is constitutively expressed in tubular epithelial cells, and its expression is enhanced following tubular injuries. In addition, clusterin has been detected in glomerular immune deposits of glomerulonephritis. The present study was designed to define the sites of clusterin mRNA accumulation in murine lupus-like nephritis in comparison with murine tubulopathies. In lupus-like nephritis, a significant increase of clusterin mRNA abundance was demonstrated. This up-regulation was localized exclusively in tubular epithelial cells exhibiting tubulointerstitial alterations, whereas no clusterin mRNA was detectable in diseased glomeruli, excluding an active synthesis of clusterin by glomerular cells. A similar tubular increase of clusterin mRNA abundance was observed in myeloma-like cast nephropathy induced by IgG3 monoclonal cryoglobulins and even in the absence of any detectable histological alterations in a model of septic shock induced by the injection of bacterial lipopolysaccharides. Our results suggest that tubular epithelial cells are the only sites of clusterin mRNA accumulation during the course of lupus-like nephritis and that the tubular up-regulation of clusterin gene expression may reflect the cellular response to various types of tubular injuries.     

HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cells

The family of small heat shock proteins (sHsp) is composed of 10 members in mammals, four of which are found mutated in diseases associated with the accumulation of protein aggregates. Though many sHsp have demonstrated molecular chaperone activity in vitro in cell-free conditions, their activity in vivo in the normal cellular context remains unclear. In the present study, we investigated the capacity of the sHsp, HspB8/Hsp22, to prevent protein aggregation in the cells using the polyglutamine protein Htt43Q as a model. In control conditions, Htt43Q accumulated in perinuclear inclusions composed of SDS-insoluble aggregates. Co-transfected with Htt43Q, HspB8 became occasionally trapped within the inclusions; however, in most cells, HspB8 blocked inclusion formation. Biochemical analyses indicated that HspB8 inhibited the accumulation of SDS-insoluble Htt43Q as efficiently as Hsp40 which was taken as a positive control. Htt43Q then accumulated in the SDS-soluble fraction, provided that protein degradation was blocked by proteasome and autophagy inhibitors. In contrast, the other sHsp Hsp27/HspB1 and alphaB-crystallin/HspB5 had no effect. This suggested that HspB8 functions as a molecular chaperone, maintaining Htt43Q in a soluble state competent for rapid degradation. Analyses of Hsp27-HspB8 chimeric proteins indicated that the C-terminal domain of HspB8 contains the specific sequence necessary for chaperone activity. Missense mutations in this domain at lysine 141, which are found in human motor neuropathies, significantly reduced the chaperone activity of the protein. A decrease in the HspB8 chaperone activity may therefore contribute to the development of these diseases.     

Endosomal sorting related protein CHMP2B is localized in Lewy bodies and glial cytoplasmic inclusions in α-synucleinopathy

Charged multivesicular body protein 2B (CHMP2B) is a component of the endosomal sorting complex required for transport-III, which is involved in the degradation of proteins in the endocytic and autophagic pathways. Mutations in the CHMP2B gene cause frontotemporal dementia and amyotrophic lateral sclerosis characterized by accumulation of ubiquitinated protein aggregates. Recent studies have shown that autophagosomal proteins are present in α-synuclein aggregates in neurons and glial cells in Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). We therefore immunohistochemically examined the brains of various neurodegenerative diseases using CHMP2B-specific antibody. CHMP2B immunoreactivity was present in intracytoplasmic and axonal Lewy bodies in PD and DLB as well as in neuronal and glial cytoplasmic inclusions in MSA. No CHMP2B immunoreactivity was found in a variety of other neuronal and glial inclusions in TDP-43 proteinopathy and tauopathy. These findings suggest that endosomal and autophagic pathway is associated with degradation or formation of α-synuclein aggregates in α-synucleinopathy.     

Expression of the small heat-shock protein alphaB-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.     

Behavioral abnormalities precede neuropathological markers in rats transgenic for Huntington's disease

Huntington's disease (HD) is caused by an expanded CAG repeatleading to the synthesis of an aberrant protein and to the formationof polyglutamine (polyQ)-containing inclusions and aggregates.Limited information is available concerning the associationof neuropathological markers with the development of behavioralmarkers in HD. Using a previously generated transgenic rat modelof HD (tgHD rat), we performed association studies on the time-courseof behavioral symptoms (motor function, learning, anxiety) andthe appearance of striatal atrophy, 1C2 immunopositive aggregatesand polyQ recruitment sites, a precursor to these aggregates.At the age of 1 month, tgHD rats exhibited reduced anxiety andimproved motor performance, while at 6 months motor impairmentsand at 9 months cognitive decline occurred. In contrast, polyQrecruitment sites appeared at around 6–9 months of age,indicating that HD-like behavioral markers preceded the appearanceof currently detectable neuropathological markers. Interestingly,numerous punctate sites containing polyQ aggregates were alsoseen in areas receiving afferents from the densely recruitingregions suggesting either transport of recruitment-competentaggregates to terminal projections where initially 1C2 positiveaggregates were formed or different internal properties of neuronsin different regions. Furthermore, striatal atrophy was observedat the age of 12 months. Taken together, our findings supportthe hypothesis of a dynamic process leading to region- and age-specificpolyQ recruitment and aggregation. The dissociation of onsetbetween behavioral and neuropathological markers is suggestiveof as yet undetected processes, which contribute to the earlyphenotype of these HD transgenic rats.     

细胞自噬参与蛋白降解及抗原递呈的研究进展

自噬是广泛存在于真核细胞中的一条胞内蛋白的降解途径,它主要对体内的长寿蛋白及一些细胞器进行降解。某些疾病的病理机制与细胞内蛋白的异常聚积并形成聚集体和包涵体有关,其分子机制与p62、LC3及其参与的细胞自噬异常有关。细胞自噬及其形成的自噬小体不仅与MHCⅡ类分子抗原提呈途径有关,而且与专职APC细胞对MHCI类分子的交叉提呈途径有关。     

alpha-synuclein aggregation: a link between mitochondrial defects and Parkinson's disease?

Protein aggregation is a shared feature of many human neurodegenerative diseases and appears to be an inevitable consequence of excessive accumulation of misfolded proteins. Recent studies suggest that accumulation of fibrillar alpha-synuclein aggregates is associated with Parkinson's disease and other Lewy body diseases. Furthermore, the missense mutations in alpha-synuclein that are responsible for some early-onset familial types of the disease promote the aggregation process of this protein. Therefore, the mechanism underlying the cellular alpha-synuclein aggregation is of great importance in understanding the pathogenic process of these diseases. This review summarizes recent advances in our understanding of the mechanisms underlying alpha-synuclein aggregation and how the mitochondrial dysfunction plays a role in this process. Protein misfolding and aggregation in vivo can be suppressed and promoted by several factors, such as molecular chaperones, protein degradation systems, and free radicals. Many of these factors are under the control of normal mitochondrial function, prompting the speculation that mitochondrial dysfunction might cause the accumulation of protein aggregates. Recent studies indeed show that mitochondrial defects can lead to the aggregation of alpha-synuclein. In addition, potentially toxic effects of alpha-synuclein have been linked to the aggregated forms rather than the monomers, both in vitro and in cultured cells. Therefore, it is postulated that aggregation of alpha-synuclein might be one of many possible links that connect mitochondrial dysfunction to neurodegeneration.     

CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation

Molecular chaperones, ubiquitin ligases and proteasome impairment have been implicated in several neurodegenerative diseases, including Alzheimer's and Parkinson's disease, which are characterized by accumulation of abnormal protein aggregates (e.g. tau and alpha-synuclein respectively). Here we report that CHIP, an ubiquitin ligase that interacts directly with Hsp70/90, induces ubiquitination of the microtubule associated protein, tau. CHIP also increases tau aggregation. Consistent with this observation, diverse of tau lesions in human postmortem tissue were found to be immunopositive for CHIP. Conversely, induction of Hsp70 through treatment with either geldanamycin or heat shock factor 1 leads to a decrease in tau steady-state levels and a selective reduction in detergent insoluble tau. Furthermore, 30-month-old mice overexpressing inducible Hsp70 show a significant reduction in tau levels. Together these data demonstrate that the Hsp70/CHIP chaperone system plays an important role in the regulation of tau turnover and the selective elimination of abnormal tau species. Hsp70/CHIP may therefore play an important role in the pathogenesis of tauopathies and also represents a potential therapeutic target.