Loss of Hsp70 Exacerbates Pathogenesis But Not Levels of Fibrillar Aggregates in a Mouse Model of Huntington's Disease

Wacker, Jennifer L.; Huang, Shao-Yi; Steele, Andrew D.; Aron, Rebecca; Lotz, Gregor P.; Nguyễn, Quang Vũ; Giorgini, Flaviano; Roberson, Erik D.; Lindquist, Susan; Masliah, Eliezer; Muchowski, Paul J.

doi:10.1523/jneurosci.2250-09.2009

Cited by 101 publications

(87 citation statements)

References 58 publications

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“…Hsp70 and Hsp40 are major cytosolic molecular chaperones that, if overexpressed, suppress neurodegeneration in animal models of polyQ diseases (16 -19). In contrast, deletion of Hsp70 markedly worsens pathogenesis in a mouse model of HD (20).…”

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confidence: 93%

Hsp70 and Hsp40 Functionally Interact with Soluble Mutant Huntingtin Oligomers in a Classic ATP-dependent Reaction Cycle

Lotz

Legleiter

Aron

et al. 2010

Journal of Biological Chemistry

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Inclusion bodies of aggregated mutant huntingtin (htt) fragments are a neuropathological hallmark of Huntington disease (HD). The molecular chaperones Hsp70 and Hsp40 colocalize to inclusion bodies and are neuroprotective in HD animal models. How these chaperones suppress mutant htt toxicity is unclear but might involve direct effects on mutant htt misfolding and aggregation. Using size exclusion chromatography and atomic force microscopy, we found that mutant htt fragments assemble into soluble oligomeric species with a broad size distribution, some of which reacted with the conformation-specific antibody A11. Hsp70 associated with A11-reactive oligomers in an Hsp40-and ATP-dependent manner and inhibited their formation coincident with suppression of caspase 3 activity in PC12 cells. Thus, Hsp70 and Hsp40 (DNAJB1) dynamically target specific subsets of soluble oligomers in a classic ATP-dependent reaction cycle, supporting a pathogenic role for these structures in HD.The accumulation of aggregated mutant htt in cytoplasmic and intranuclear inclusion bodies in neurons is a pathological hallmark of HD. 4 Recent studies suggest that mutant htt is a highly dynamic protein that adopts multiple misfolded monomeric and higher order conformations that exist in a dynamic equilibrium (1, 2). Which of these structures, if any, mediate toxic gain-of-function protein interactions that cause neuronal dysfunction and cell death in HD is not well understood.The assembly of mutant htt into amyloid-like fibrils was initially thought to be causally associated with the pathogenesis of HD (3, 4). More recent studies indicate that mutant htt and other disease-associated proteins with polyglutamine (polyQ) expansions also exist as smaller oligomers that have spherical, annular, and protofibrillar morphologies (5-7) that might be less energetically stable and more chemically reactive (and toxic) than fibrils. Consistent with this scenario, in cell and mouse models of HD, misfolded species of mutant htt in a diffuse fraction impair cellular machinery before fibrils accumulate (8 -10). In a cellular model of HD, the survival rate of cells is greater in the presence of inclusion bodies that contain fibrils than in their absence (11). Importantly, mutant htt fragments and synthetic polyQ peptides form oligomers in a polyQ lengthdependent manner in vitro and in vivo, consistent with a causative role for these structures in HD pathogenesis (2). However, oligomers are also highly heterogeneous in size, stability, and solubility (2). Therefore, only subsets of such structures might be most biologically active.Many disease-causing proteins form toxic oligomers that react in a conformation-dependent manner with A11, an antibody that neutralizes their toxicity in cell-based assays (12). Thus, the misfolding of disease proteins to a similar oligomeric conformation might contribute to their toxicity. The molecular mechanism for this misfolding is not clear, but A11 seems to recognize a structural motif that is exposed only in oligomers and not in ...

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confidence: 93%

Hsp70 and Hsp40 Functionally Interact with Soluble Mutant Huntingtin Oligomers in a Classic ATP-dependent Reaction Cycle

Lotz

Legleiter

Aron

et al. 2010

Journal of Biological Chemistry

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“…For instance, overexpression of Hsp70 and Hsp40 suppresses neurodegeneration in animal models of polyglutamine diseases (8,9). In parallel, deletion of Hsp70 markedly worsens pathogenesis in a mouse model of HD (10). Chaperones are thought to suppress the toxicity of disease-associated proteins through direct effects on their misfolding and clearance; however, the mechanisms are not well understood.…”

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confidence: 99%

Exogenous delivery of chaperonin subunit fragment ApiCCT1 modulates mutant Huntingtin cellular phenotypes

Sontag

Joachimiak

Tan

et al. 2013

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

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Aggregation of misfolded proteins is characteristic of a number of neurodegenerative diseases, including Huntington disease (HD). The CCT/TRiC (chaperonin containing TCP-1/TCP-1 ring) chaperonin complex can inhibit aggregation and cellular toxicity induced by expanded repeat Huntingtin (mHtt) fragments. The substratebinding apical domain of CCT/TRiC subunit CCT1, ApiCCT1, is sufficient to inhibit aggregation of expanded repeat mHtt fragments in vitro, providing therapeutic promise for HD. However, a key hurdle in considering ApiCCT1 as a potential treatment is in delivery. Because ApiCCT1 has a region of similarity to the HIV Tat protein cell-transduction domain, we tested whether recombinant ApiCCT1 (ApiCCT1 r ) protein could enter cells following exogenous delivery and modulate an established panel of mHtt-mediated cell-based phenotypes. Cell fractionation studies demonstrate that exogenous ApiCCT1 r can penetrate cell membranes and can localize to the nucleus, consistent with a strategy that can target both cytosolic and nuclear pathogenic events in HD. ApiCCT1 r application does indeed modulate HD cellular phenotypes by decreasing formation of visible inclusions, fibrillar oligomers, and insoluble mHtt derived from expression of a truncated mHtt exon 1 fragment. ApiCCT1 r also delays the onset of inclusion body formation as visualized via live imaging. ApiCCT1 r reduces mHtt-mediated toxicity in immortalized striatal cells derived from full-length knock-in HD mice, suggesting that therapeutic benefit may extend beyond effects on aggregation. These studies provide the basis for a potentially robust and unique therapeutic strategy to target mHtt-mediated protein pathogenesis.

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“…Endogenous heat shock proteins (Hsps) exert neuroprotective activity in rodent models of Huntington's disease, Amyotrophic Lateral Sclerosis, and other cases of neuropathologies (Cummings et al 2001;Franklin et al 2005;Wacker et al 2009;Gifondorwa et al 2007). In a cellular model of AD, Hsp70 overexpression effectively protected neurons from accumulation of Аβ (Magrané et al 2004;Hoshino et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Dynamics of endogenous Hsp70 synthesis in the brain of olfactory bulbectomized mice

Бобкова

Guzhova

Margulis

et al. 2013

Cell Stress and Chaperones

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Numerous epidemiological studies have established acute brain injury as one of the major risk factors for the Alzheimer's disease (AD). However, the lack of animal models of AD-like degeneration triggered by a defined injury hampered the development of adequate therapies. Here we report that the surgical damage of the olfactory bulbs triggers the development of several pathologies, including amyloid-β accumulation and strong decrease of neuron density in the cortex and hippocampus as well as significant disturbance of spatial memory. Characteristically, these harmful consequences of the olfactory bulbectomy (OBX) have a peculiar dynamics in time with maximal manifestation in periods of 1-1.5 months and 8 months after the surgery and, hence, exhibit biphasic pattern with almost complete recovery period taking place at 5-6 months after the operation. The quantitative determination of endogenous inducible form of Hsp70 in different brain areas of OBX mice demonstrated characteristic fluctuations of Hsp70 levels depending on the time after the operation and age of mice. Interestingly, maximal induction of Hsp70 synthesis in the hippocampus exhibits clear-cut coincidence with the recovery period in OBX animals. The observed correlation enables to suggest curing effect of Hsp70 synthesis at an earlier period of pathology development and establishes it as a possible therapeutic agent for secondary grave consequences of brain injury, such as AD-like degeneration, for which neuroprotective therapy is urgently needed.

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Loss of Hsp70 Exacerbates Pathogenesis But Not Levels of Fibrillar Aggregates in a Mouse Model of Huntington's Disease

Cited by 101 publications

References 58 publications

Hsp70 and Hsp40 Functionally Interact with Soluble Mutant Huntingtin Oligomers in a Classic ATP-dependent Reaction Cycle

Hsp70 and Hsp40 Functionally Interact with Soluble Mutant Huntingtin Oligomers in a Classic ATP-dependent Reaction Cycle

Exogenous delivery of chaperonin subunit fragment ApiCCT1 modulates mutant Huntingtin cellular phenotypes

Dynamics of endogenous Hsp70 synthesis in the brain of olfactory bulbectomized mice

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