Neuroprotection by Hsp104 and Hsp27 in Lentiviral-based Rat Models of Huntington's Disease

Abstract

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expansion of glutamine repeats in the huntingtin (htt) protein. Abnormal protein folding and the accumulation of mutated htt are hallmarks of HD neuropathology. Heat-shock proteins (hsps), which refold denatured proteins, might therefore mitigate HD. We show here that hsp104 and hsp27 rescue striatal dysfunction in primary neuronal cultures and HD rat models based on lentiviral-mediated overexpression of a mutated htt fragment. In primary rat striatal cultures, production of hsp104 or hsp27 with htt171-82Q restored neuronal nuclei (NeuN)-positive cell density to that measured after infection with vector expressing the wild-type htt fragment (htt171-19Q). In vivo, both chaperones significantly reduced mutated-htt-related loss of DARPP-32 expression. Furthermore, hsps affected the distribution and size of htt inclusions, with the density of neuritic aggregates being remarkably increased in striatal neurons overexpressing hsps. We also found that htt171-82Q induced the up-regulation of endogenous hsp70 that was co-localized with htt inclusions, and that the overexpression of hsp104 and hsp27 modified the subcellular localization of hsp70 that became cytoplasmic. Finally, hsp104 induced the production of endogenous hsp27. These data demonstrate the protective effects of chaperones in mammalian models of HD.

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

“…The accumulation of misfolded proteins that have amyloid characteristics (a tertiary structure that is rich in β-sheets and can be visualized by staining with dyes such as Congo red and Thioflavin S) is thought to result from improper folding of the mutant proteins as well as insufficient clearance mechanisms 129 . Endogenous chaperones, in particular the heat-shock proteins, prevent misfolding and aggregation of mHtt, Tau and Aβ 130 , and their overexpression is protective against neurotoxic insults such as excitotoxicity 131 (Suppl Table S4). …”

Hsp104 Targets Multiple Intermediates on the Amyloid Pathway and Suppresses the Seeding Capacity of Aβ Fibrils and Protofibrils

“…4,[36][37][38] Discussion ClpB/Hsp104 proteins have the ability to modulate aggregate formation and toxicity and to "catalyze" the disaggregation and recovery of protein aggregates in yeast, 12 Escherichia coli, 39 mammalian cell cultures, and animal models of HD and Parkinson's disease. [16][17][18][19][20] Several mechanistic models have been proposed to explain these experimental observations. These models include (i) Hsp104-mediated inhibition of protein misfolding and aggregation, (ii) diversion of proteins towards non-toxic pathways, and (iii) disruption and dissociation of prefibrillar and fibrillar toxic aggregates.…”

“…Huntington's disease (HD)], mammalian cell cultures, and yeast models of HD. [16][17][18][19][20] Others have shown that Hsp104 alone can disassemble preformed Sup35 and Ure2 prion fibrils. 2,3 However, the molecular mechanisms underlying these effects remain poorly understood (Scheme 1c).…”

Molecular chaperones and neuronal proteostasis

“…small HSP HSP27 (HSPB1) AD/ Aβ Reduced Aβ aggregation in vitro and toxicity on cells [98] and in mice [99]; alters tau dynamics in mice [100]; reduced polyQ aggregation and toxicity in cells [101] and by viral delivery in rats [102] but not transgenic mice [103]; reduced α-synuclein fibril AD/Tau HD/Htt AD deficits in mice [120]; polyQ in mice [121]; mutant SOD1 in mice [122].…”