The Chaperone Activity of Heat Shock Protein 90 Is Critical for Maintaining the Stability of Leucine-Rich Repeat Kinase 2

• DOI: 10.1523/jneurosci.0185-08.2008
• Publication Date: 2008-03-26T16:36:32Z
• Authors: Lizhen Wang; Chengsong Xie; Elisa Greggio; Loukia Parisiadou; Hoon Shim; Lixin Sun; Jayanth Chandran; Xian Lin; Chen Lai; Wan-Jou Yang; Darren J. Moore; Ted M. Dawson; Valina L. Dawson; Gabriela Chiosis; Mark R. Cookson; Huaibin Cai
• Keywords: LRRK2; Protein kinase domain; Leucine-rich repeat

Parkinson's disease (PD), a progressive neurodegenerative characterized by bradykinesia, rigidity, and resting tremor, is the most common movement disorder. Although majority of PD cases are sporadic, some inherited, including those caused leucine-rich repeat kinase 2 (LRRK2) mutations. The substitution serine for glycine at position 2019 (G2019S) in domain LRRK2 represents prevalent genetic mutation both familial apparently sporadic PD. Because mutations likely associated with toxic gain function, destabilization may be novel way to limit its detrimental effects. Here we show that forms complex heat shock protein 90 (Hsp90) vivo inhibition Hsp90 disrupts association leads proteasomal degradation LRRK2. inhibitors therefore mutant LRRK2-elicited toxicity neurons. As proof principle, rescue axon growth retardation overexpression G2019S Therefore, activity can achieved blocking Hsp90-mediated chaperone serve as potential anti-PD drugs.