Abstract
Parkinson's disease is a neurodegenerative disorder characterized by Lewy bodies, a pathological hallmark comprised mostly of aggregated alpha synuclein. Accumulating evidence demonstrates the association of smaller oligomeric aggregates to disease etiology and many therapeutic approaches are aimed at inhibiting and reducing the aggregation process. Molecular chaperones and co-chaperones play a key role in protein homeostasis and have potential as therapeutics to inhibit alpha synuclein associated toxicity. Here we use a gene therapy approach to evaluate the applicability of the Hsp70 co-chaperone CHIP (C-terminal Hsp70 interacting protein) as a therapeutic candidate and examine its direct effect on alpha synuclein aggregates in vivo. Utilizing a novel viral vector mediated rat model to directly detect alpha synuclein aggregates, we show that CHIP can mediate the degradation of alpha synuclein aggregates in vivo. However, our studies also reveal that CHIP may potentially degrade tyrosine hydroxylase which would compromise the applicability of CHIP as a therapeutic approach for Parkinson's disease.
Highlights
Many neurodegenerative diseases share the common characteristic of protein misfolding and consequent aggregation leading to cell death
In the current study we examine if the Hsp70 co-chaperone protein C-terminus Hsp70 interacting protein (CHIP) can reduce a-syn oligomerization and concomitantly rescue a-syn–induced neurotoxicity in vivo
In the same regions of interest (ROIs), a-syn immunostaining was reduced by 15% in CHIP expressing animals compared to control animals (Fig. 1C)
Summary
Many neurodegenerative diseases share the common characteristic of protein misfolding and consequent aggregation leading to cell death. Having previously demonstrated the ability of the co-chaperone C-terminus Hsp interacting protein (CHIP) to target toxic a-syn aggregates for degradation in vitro [8,9], we describe the modulation of a-syn aggregates by CHIP in vivo in a novel viral-vector mediated rat model [10]. In this model the direct detection of a-syn aggregates using in vivo protein-fragment complementation facilitates the examination and quantitation of CHIP-induced modulation of asyn aggregates in vivo. We demonstrate the direct visualization of a-syn degradation in vivo and validate the applicability of our animal model in examining potential therapeutic approaches that target a-syn aggregates
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