Analysis of the Role of Heat Shock Protein (Hsp) Molecular Chaperones in Polyglutamine Disease

Chai, Yaohui; Koppenhafer, Stacia L.; Bonini, Nancy M.; Paulson, Henry L.

doi:10.1523/jneurosci.19-23-10338.1999

Cited by 402 publications

(281 citation statements)

References 42 publications

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“…The suppression is particularly striking when HDJ-1, a member of the Hsp40 chaperone family, is overexpressed. Suppression of aggregate formation by Hsp40 has previously been demonstrated in in vitro models of polyglutamine disease (Cummings et al 1998;Chai et al 1999). Hsp40 is a cochaperone for Hsp70 and binds to and stimulates the ATPase activity of Hsp70 (Cyr et al 1994).…”

Section: Discussionmentioning

confidence: 90%

“…A role for HSPs in neurodegenerative diseases involving protein aggregation has been suggested by recent studies. Hsp40 and Hsp70 were found to localize to nuclear inclusions formed by mutant ataxin-1 and ataxin-3 in spinocerebellar ataxia types 1 and 3 (Cummings et al 1998;Chai et al 1999). Moreover, cell culture studies demonstrated that overexpression of HDJ-2 suppressed the aggregation of mutant ataxin-1, while that of HDJ-1 and HDJ-2 decreased aggregation of mutant ataxin-2, and a combination of HDJ-1 and Hsp70 prevented the aggregation of mutant androgen receptor in spinobulbar muscular atrophy (Chai et al 1999;Cummings et al 1998;Kobayashi et al 2000).…”

mentioning

confidence: 98%

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TorsinA and heat shock proteins act as molecular chaperones: suppression of α‐synuclein aggregation

McLean

Kawamata

Shariff

et al. 2002

Journal of Neurochemistry

312

241

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TorsinA, a protein with homology to yeast heat shock protein104, has previously been demonstrated to colocalize with a-synuclein in Lewy bodies, the pathological hallmark of Parkinson's disease. Heat shock proteins are a family of chaperones that are both constitutively expressed and induced by stressors, and that serve essential functions for protein refolding and/or degradation. Here, we demonstrate that, like torsinA, specific molecular chaperone heat shock proteins colocalize with a-synuclein in Lewy bodies. In addition, using a cellular model of a-synuclein aggregation, we demonstrate that torsinA and specific heat shock protein molecular chaperones colocalize with a-synuclein immunopositive inclusions. Further, overexpression of torsinA and specific heat shock proteins suppress a-synuclein aggregation in this cellular model, whereas mutant torsinA has no effect. These data suggest that torsinA has chaperone-like activity and that the disease-associated GAG deletion mutant has a loss-of-function phenotype. Moreover, these data support a role for chaperone proteins, including torsinA and heat shock proteins, in cellular responses to neurodegenerative inclusions.

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Section: Discussionmentioning

confidence: 90%

mentioning

confidence: 98%

TorsinA and heat shock proteins act as molecular chaperones: suppression of α‐synuclein aggregation

McLean

Kawamata

Shariff

et al. 2002

Journal of Neurochemistry

312

241

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“…One can envision that transfer of nonfoldable substrates to HSP70 would result in a fatuous ATP‐driven substrate binding and release, which may slightly delay aggregation but not prevent it. Indeed, in cells overexpression of HSP70s only marginally affects polyQ aggregation (Chai et al ., 1999; Rujano et al ., 2007), whereas in vivo HSP70‐mediated rescue of polyQ toxicity only occurs in the presence of semi‐soluble nuclear polyQ aggregates (Warrick et al ., 1999; Chan et al ., 2000; Cummings et al ., 2001). Thus, the different small HSPs with different affinities to substrates and HSP70s may have evolved to serve adequate processing of a broad spectrum of clients.…”

Section: Discussionmentioning

confidence: 99%

Specific protein homeostatic functions of small heat‐shock proteins increase lifespan

et al. 2015

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SummaryDuring aging, oxidized, misfolded, and aggregated proteins accumulate in cells, while the capacity to deal with protein damage declines severely. To cope with the toxicity of damaged proteins, cells rely on protein quality control networks, in particular proteins belonging to the family of heat‐shock proteins (HSPs). As safeguards of the cellular proteome, HSPs assist in protein folding and prevent accumulation of damaged, misfolded proteins. Here, we compared the capacity of all Drosophila melanogaster small HSP family members for their ability to assist in refolding stress‐denatured substrates and/or to prevent aggregation of disease‐associated misfolded proteins. We identified CG14207 as a novel and potent small HSP member that exclusively assisted in HSP70‐dependent refolding of stress‐denatured proteins. Furthermore, we report that HSP67BC, which has no role in protein refolding, was the most effective small HSP preventing toxic protein aggregation in an HSP70‐independent manner. Importantly, overexpression of both CG14207 and HSP67BC in Drosophila leads to a mild increase in lifespan, demonstrating that increased levels of functionally diverse small HSPs can promote longevity in vivo.

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“…In mammalian cells, both members of the Hsp40 family are associated with aggregates of glutamine-expansion proteins, and their overexpression suppresses polyQ aggregation (26,28). Interestingly, in the only study that directly compared the effects of HDJ1 and HDJ2, HDJ1 (the Sis1 homologue) had a much stronger effect than HDJ2 (the Ydj1 homologue) (43). Overexpression of Hsp70 in yeast had a stronger effect on HtQ72 and HtQ103 localization than any of the Hsp40 manipulations we tested.…”

Section: Discussionmentioning

confidence: 99%

Aggregation of huntingtin in yeast varies with the length of the polyglutamine expansion and the expression of chaperone proteins

Krobitsch

Lindquist

2000

Proc. Natl. Acad. Sci. U.S.A.

515

438

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P olyglutamine (polyQ) expansions in several unrelated proteins are responsible for at least eight inherited neurodegenerative diseases. These include Huntington's disease (HD), spinobulbar muscular atrophy, dentatorubral pallidoluysian atrophy, and spinocerebellar ataxia types 1, 2, 3, 6, and 7 (1-3). Perhaps the most baffling aspect of these diseases is that the proteins are expressed widely in brain and other tissues, yet each is toxic in a different, highly specific group of neurons and produces a distinct pathology (2).The major characteristic of HD is a selective loss of neurons in the striatum and cortex leading to movement disorders, dementia, and eventually, death (4, 5). The causative agent is a 350-kDa protein, huntingtin (Ht), with glutamine expansions in the N-terminal region (6). The toxicity of Ht in specific neurons correlates with the length of the glutamine expansion, but the mechanism of toxicity is unknown (7,8).A central event in HD is the production of an N-terminal fragment of Ht that aggregates in affected neurons during the natural progression of the disease in humans (9). In transgenic animal models an N-terminal fragment is sufficient to produce an HD-like phenotype, which also depends on the length of the Q repeat (10, 11). Aggregates are found in both the nucleus and/or the cytoplasm of affected neurons in human patients, transgenic animals, and cell lines (12). It is by no means clear, however, whether the aggregates are themselves pathogenic, simply benign byproducts (and thereby markers) of other pathogenic polyQ misfolding events, or a defense mechanism whose purpose is to reduce the interaction of toxic misfolded polyQ proteins with other proteins.Indeed, even the mechanisms underlying the aggregation of these fragments are unknown. A further complexity is that several other proteins interact with Ht. These include HAP1, HIP1, Hsp35, WW domain-containing proteins, the ubiquitin-conjugating enzyme hE2-25k, the SH3GL3 protein, cystathione ␤-synthase, and calmodulin (12)(13)(14).These problems are inherently difficult to study. Although several mammalian cell-line and transgenic-animal models exist for studying Ht, none is as readily amenable to genetic analysis as yeast. We demonstrate that the aggregation of N-terminal fragments of Ht in yeast cells depends on the length of its polyQ repeat and that this aggregation depends on the balance of chaperone protein activities in the cell. Furthermore, N-terminal fragments with up to 103 glutamines have little or no toxicity in either the aggregated or the soluble state. Thus, yeast cells should provide a valuable system for investigating general factors that affect aggregation and for determining what neuronal cell-type specific factors might inf luence toxicity. Materials and MethodsPlasmid Construction. Plasmids encoding fusions between the N-terminal region of Ht and green fluorescent protein (GFP) were the kind gift of G. Lawless (Univ. of California, Los Angeles).To create yeast expression plasmids for HtQ25 or HtQ103, DNAs were d...

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Analysis of the Role of Heat Shock Protein (Hsp) Molecular Chaperones in Polyglutamine Disease

Cited by 402 publications

References 42 publications

TorsinA and heat shock proteins act as molecular chaperones: suppression of α‐synuclein aggregation

TorsinA and heat shock proteins act as molecular chaperones: suppression of α‐synuclein aggregation

Specific protein homeostatic functions of small heat‐shock proteins increase lifespan

Aggregation of huntingtin in yeast varies with the length of the polyglutamine expansion and the expression of chaperone proteins

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