Direct visualization of CHIP-mediated degradation of alpha-synuclein in vivo: Implications for PD therapeutics

Hemi Dimant, Liya Zhu, Laura N. Kibuuka, Zhanyun Fan, Bradley T. Hyman, Pamela J McLean

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere92098
JournalPLoS One
Volume9
Issue number3
DOIs
StatePublished - Mar 24 2014

Fingerprint

alpha-Synuclein
Proteolysis
protein aggregates
Visualization
Degradation
therapeutics
degradation
Parkinson disease
Proteins
proteins
Parkinson Disease
tyrosine 3-monooxygenase
Therapeutics
Lewy Bodies
Gene therapy
molecular chaperones
Molecular Chaperones
gene therapy
neurodegenerative diseases
Tyrosine 3-Monooxygenase

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Direct visualization of CHIP-mediated degradation of alpha-synuclein in vivo : Implications for PD therapeutics. / Dimant, Hemi; Zhu, Liya; Kibuuka, Laura N.; Fan, Zhanyun; Hyman, Bradley T.; McLean, Pamela J.

In: PLoS One, Vol. 9, No. 3, e92098, 24.03.2014.

Research output: Contribution to journalArticle

Dimant, Hemi ; Zhu, Liya ; Kibuuka, Laura N. ; Fan, Zhanyun ; Hyman, Bradley T. ; McLean, Pamela J. / Direct visualization of CHIP-mediated degradation of alpha-synuclein in vivo : Implications for PD therapeutics. In: PLoS One. 2014 ; Vol. 9, No. 3.
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