Chaperone Suppression of α-Synuclein Toxicity in a Drosophila Model for Parkinson's Disease

Abstract

Parkinson's disease is a movement disorder characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta. Dopaminergic neuronal loss also occurs in Drosophila melanogaster upon directed expression of alpha-synuclein, a protein implicated in the pathogenesis of Parkinson's disease and a major component of proteinaceous Lewy bodies. We report that directed expression of the molecular chaperone Hsp70 prevented dopaminergic neuronal loss associated with alpha-synuclein in Drosophila and that interference with endogenous chaperone activity accelerated alpha-synuclein toxicity. Furthermore, Lewy bodies in human postmortem tissue immunostained for molecular chaperones, also suggesting that chaperones may play a role in Parkinson's disease progression.

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

“…We demonstrate that specific HSP molecular chaperones immunolocalize with a-synuclein in LB in substantia nigra. These findings are in agreement with the recent report that Lewy body inclusions in Parkinson's disease and related disorders are immunopositive for Hsp70 and Hsp40 (Auluck et al 2002).…”

“…Specifically, torsinA immunoreactivity has been previously demonstrated in LB of PD and DLB patients (Shashidharan et al 2000;Sharma et al 2001) and we demonstrate here that a-synuclein immunopositive inclusions are also torsinA immunoreactive in a cell culture model. Furthermore, Hsp70 has recently been demonstrated to colocalize to LB in Drosophila brain and Hsp70 and Hsp40 were found to localize with LB in human brain (Auluck et al 2002). In agreement with this study, we found that Hsp70 and Hsp40 family members, HDJ-1 and HDJ-2, localized with LB in human DLB brain.…”

“…A role for chaperone involvement in neurodegenerative diseases is further supported by the recent study that demonstrated that coexpression of Hsp70 can suppress dopaminergic cell death in a Drosophila model of Parkinson's disease (Auluck et al 2002). In contrast to our present study, there was no effect on the number or size of Lewy body-like inclusions when Hsp70 was coexpressed with a-synuclein in Drosophila.…”

Firefly luciferase mutants as sensors of proteome stress

“…Hsp70 members are highly multifunctional proteins that have been shown to play a key role in proteome maintenance, such as in de novo protein folding (co-or post-translational), protein translocation across membranes (Lyman and Schekman, 1997;Matlack et al, 1999;Young et al, 2003), refolding of stress damaged proteins (Ben-Zvi et al, 2004;Schroder et al, 1993;Sharma et al, 2010), in preventing protein aggregation (Auluck et al, 2002;Broadley and Hartl, 2009;Klucken et al, 2004;Sakahira et al, 2002;Warrick et al, 1999), disaggregation (Ben-Zvi and Goloubinoff, 2001;Diamant et al, 2000;Liberek et al, 2008;Shorter, 2011) and degradation of irreparable misfolded proteins (Bercovich et al, 1997;Fisher et al, 1997;Urushitani et al, 2004). These essential and diverse cellular functions of Hsp70 are attributed to its physical interaction with various co-chaperones such as Hsp40, NEFs and with proteins such as HIP, HOP and CHIP.…”

Gene therapy progress and prospects: Parkinson's disease

“…37 Work in Drosophila may accelerate understanding of the human disease by identifying candidate pathways for disease modification. 38 The genetic forms of PD are uncommon, but gene therapy targeting the a-synuclein, Parkin or other pathways may also turn out to be an appropriate intervention for idiopathic PD. Using a-synuclein transgenic mice, it was shown that overexpression of b-synuclein prevented aggregation of a-synuclein and the resulting abnormal phenotype.…”