Applying Hsp104 to protein-misfolding disorders

Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 805b Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, USA.
Biochemistry and Cell Biology (Impact Factor: 2.15). 02/2010; 88(1):1-13. DOI: 10.1139/o09-121
Source: PubMed


Hsp104, a hexameric AAA+ ATPase found in yeast, transduces energy from cycles of ATP binding and hydrolysis to resolve disordered protein aggregates and cross-beta amyloid conformers. These disaggregation activities are often co-ordinated by the Hsp70 chaperone system and confer considerable selective advantages. First, renaturation of aggregated conformers by Hsp104 is critical for yeast survival after various environmental stresses. Second, amyloid remodeling by Hsp104 enables yeast to exploit multifarious prions as a reservoir of beneficial and heritable phenotypic variation. Curiously, although highly conserved in plants, fungi and bacteria, Hsp104 orthologues are absent from metazoa. Indeed, metazoan proteostasis seems devoid of a system that couples protein disaggregation to renaturation. Here, we review recent endeavors to enhance metazoan proteostasis by applying Hsp104 to the specific protein-misfolding events that underpin two deadly neurodegenerative amyloidoses. Hsp104 potently inhibits Abeta42 amyloidogenesis, which is connected with Alzheimer's disease, but appears unable to disaggregate preformed Abeta42 fibers. By contrast, Hsp104 inhibits and reverses the formation of alpha-synuclein oligomers and fibers, which are connected to Parkinson's disease. Importantly, Hsp104 antagonizes the degeneration of dopaminergic neurons induced by alpha-synuclein misfolding in the rat substantia nigra. These studies raise hopes for developing Hsp104 as a therapeutic agent.

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    • "The temperature-stress-induced electron-dense inclusions that we observed are reminiscent of heat-dependent electrondense patches that have been associated with the protein disaggregase Hsp104 in S. cerevisiae (Fujita et al., 1998; Kawai et al., 1999). Hsp104 is a hexameric AAA+ ATPase that couples ATP hydrolysis to protein disaggregation (Doyle et al., 2013; Vashist et al., 2010). It mediates the resolubilization of heat-inactivated proteins from insoluble aggregates and plays an essential role in induced thermotolerance and prion propagation (Glover and Lindquist, 1998; Parsell et al., 1994; Sanchez and Lindquist, 1990). "
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    ABSTRACT: Epigenetic mechanisms can be influenced by environmental cues and thus evoke phenotypic variation. This plasticity can be advantageous for adaptation but also detrimental if not tightly controlled. Although having attracted considerable interest, it remains largely unknown if and how environmental cues such as temperature trigger epigenetic alterations. Using fission yeast, we demonstrate that environmentally induced discontinuous phenotypic variation is buffered by a negative feedback loop that involves the RNase Dicer and the protein disaggregase Hsp104. In the absence of Hsp104, Dicer accumulates in cytoplasmic inclusions and heterochromatin becomes unstable at elevated temperatures, an epigenetic state inherited for many cell divisions after the heat stress. Loss of Dicer leads to toxic aggregation of an exogenous prionogenic protein. Our results highlight the importance of feedback regulation in building epigenetic memory and uncover Hsp104 and Dicer as homeostatic controllers that buffer environmentally induced stochastic epigenetic variation and toxic aggregation of prionogenic proteins. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 12/2014; 10(1). DOI:10.1016/j.celrep.2014.12.006 · 8.36 Impact Factor
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    • "Macroautophagy (hereafter referred to as autophagy ) is also critical in PMP22-linked neuropathies as autophagosomes accumulate near protein aggregates within neuropathic Schwann cells and under permissive conditions, activating autophagy clears the misfolded PMP22 (Fortun et al., 2003, 2006, 2007). The third defense mechanism involves molecular chaperones that can prevent protein aggregation by assisting folding (Young et al., 2004) or degradation (Vashist et al., 2010). "
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    ABSTRACT: Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary demyelinating neuropathy linked with duplication of the peripheral myelin protein 22 (PMP22) gene. Transgenic C22 mice, a model of CMT1A, display many features of the human disease, including slowed nerve conduction velocity and demyelination of peripheral nerves. How overproduction of PMP22 leads to compromised myelin and axon pathology is not fully understood, but likely involves subcellular alterations in protein homeostatic mechanisms within affected Schwann cells. The subcellular response to abnormally localized PMP22 includes the recruitment of the ubiquitin-proteasome system (UPS), autophagosomes and heat shock proteins. Here we assessed biochemical markers of these protein homeostatic pathways in nerves from PMP22-overexpressing neuropathic mice between the ages of 2-12 months to ascertain their potential contribution to disease progression. In nerves of 3 week old mice, using endoglycosidases and western blotting, we found altered processing of the exogenous human PMP22, an abnormality that becomes more prevalent with age. Along with the ongoing accrual of misfolded PMP22, the activity of the proteasome becomes compromised and proteins required for autophagy induction and lysosome biogenesis are upregulated. Moreover, cytosolic chaperones are consistently elevated in nerves from neuropathic mice, with the most prominent change in HSP70. The gradual alterations in protein homeostatic response are accompanied by Schwann cell de-differentiation and macrophage infiltration. Together, these results show that while subcellular protein quality control mechanisms respond appropriately to the presence of the overproduced PMP22, with aging they are unable to prevent the accrual of misfolded proteins.
    ASN Neuro 10/2013; 5(5). DOI:10.1042/AN20130024 · 4.02 Impact Factor
    • "Ultimately, agents that can efficiently disaggregate or degrade these amyloid fibrils could be developed into a vaginal microbicide, thus reducing amyloid-mediated enhancement of HIV infectivity and offering a preventative strategy to combat HIV infection via sexual transmission. In this context, it will be interesting to explore amyloid disaggregases that can rapidly dissociate amyloid forms within a few minutes [69,119,120,121]. Here, it will be important to isolate conditions where disaggregases completely eliminate amyloid forms rather than yielding fragmented fibrils, which might enhance HIV infection [122]. "
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    ABSTRACT: Despite its discovery over 30 years ago, human immunodeficiency virus (HIV) continues to threaten public health worldwide. Semen is the principal vehicle for the transmission of this retrovirus and several endogenous peptides in semen, including fragments of prostatic acid phosphatase (PAP248-286 and PAP85-120) and semenogelins (SEM1 and SEM2), assemble into amyloid fibrils that promote HIV infection. For example, PAP248-286 fibrils, termed SEVI (Semen derived Enhancer of Viral Infection), potentiate HIV infection by up to 105-fold. Fibrils enhance infectivity by facilitating virion attachment and fusion to target cells, whereas soluble peptides have no effect. Importantly, the stimulatory effect is greatest at low viral titers, which mimics mucosal transmission of HIV, where relatively few virions traverse the mucosal barrier. Devising a method to rapidly reverse fibril formation (rather than simply inhibit it) would provide an innovative and urgently needed preventative strategy for reducing HIV infection via the sexual route. Targeting a host-encoded protein conformer represents a departure from traditional microbicidal approaches that target the viral machinery, and could synergize with direct antiviral approaches. Here, we review the identification of these amyloidogenic peptides, their mechanism of action, and various strategies for inhibiting their HIV-enhancing effects.
    Biology 12/2012; 1(1):58-80. DOI:10.3390/biology1010058
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