Endogenous Rab29 does not impact basal or stimulated LRRK2 pathway activity

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Mutations in Leucine-rich repeat kinase 2 (LRRK2) are a common cause of inherited Parkinson's disease.
• LRRK2 phosphorylates Rab GTPase proteins, including Rab10 and Rab12.
• Rab29 has been implicated in a common pathway with LRRK2, potentially regulating its activity.

Purpose of the Study:

• To investigate the role of Rab29 in regulating endogenous Leucine-rich repeat kinase 2 (LRRK2) activity.
• To determine if Rab29 deficiency impacts LRRK2 phosphorylation of Rab10 and Rab12.
• To assess the effect of Rab29 on LRRK2 activity under basal and stimulated conditions.

Main Methods:

• Assessment of Rab10 and Rab12 phosphorylation in wild-type, LRRK2[R1441C], and VPS35[D620N] knock-in mouse tissues and cell lines.
• Analysis of LRRK2 activity in Rab29 knock-out mice.
• Evaluation of LRRK2 phosphorylation following stimulation of the endolysosomal system with agents like nigericin.

Main Results:

• Rab29 knock-out did not alter endogenous LRRK2 activity, as measured by Rab10 and Rab12 phosphorylation.
• Rab12 phosphorylation was more sensitive to LRRK2 inhibitors and mutations than Rab10 phosphorylation in brain extracts.
• Stimulation of LRRK2 activity by endolysosomal stress agents was suppressed by LRRK2 inhibitors but not blocked in Rab29 deficient cells.

Conclusions:

• Basal, pathogenic, and stress-induced Leucine-rich repeat kinase 2 (LRRK2) pathway activity is not controlled by Rab29.
• Further research is needed to elucidate the regulatory mechanisms of LRRK2 activity and identify other Rab proteins that may control it.