Year: 2014
Type: article
Abstract: Parkinson's disease (PD) is the most common neurodegenerative movement disorder, characterized by progressive loss of dopaminergic neurons in the substantia nigra.Most PD cases are thought to be idiopathic with unknown etiology.About 10% of the PD cases are familial due to inheritance of genetic mutations.Mutations in LRRK2 (leucine-rich repeat kinase 2) is the most frequent known cause for the late-onset and autosomal-dominantly inherited PD.LRRK2 has been implicated in diverse molecular pathways and cellular functions, but many of its substrates are yet to be discovered.In this study, we have used a chemical genetics approach, which allows a minimally modified kinase to be sensitized to synthetic ATP analogs for phosphorylation of its direct substrates, to identify previously unidentified substrates that are specific to LRRK2.We have applied this analog-sensitive strategy and have identified many putative cellular substrates of LRRK2 in human cells using Western blot and tandem mass spectrometry.We have discovered that two of these proteins, VPS35 and eIF4G1, are encoded by the corresponding genes linked to PD.Furthermore, we have verified eIF4G1 as a novel LRRK2 substrate, suggesting that LRRK2 may play an important role in the regulation of protein translation.
Author: Caroline H. Lee
Institution: Case Western Reserve University
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2802929024