Elevated Urinary Rab10 Phosphorylation in Idiopathic Parkinson Disease

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Pathogenic leucine-rich repeat kinase 2 (LRRK2) mutations are linked to increased kinase activity and idiopathic Parkinson disease (iPD) risk.
• Genetic variations in LRRK2 influence susceptibility to iPD.

Purpose of the Study:

• To investigate changes in LRRK2 kinase activity during iPD progression using pT73-Rab10 levels in urinary extracellular vesicles.
• To establish a peripheral biomarker for LRRK2 activity in Parkinson disease.

Main Methods:

• Immunoblotting was used to measure the ratio of pT73-Rab10 to total Rab10 in urinary extracellular vesicles.
• Samples were analyzed from G2019S LRRK2 mutation carriers and a longitudinal cohort of iPD patients and controls.
• Generalized estimating equations analyzed associations with clinical scales.

Main Results:

• The G2019S LRRK2 mutation did not elevate pT73-Rab10 levels.
• A nominal increase in pT73-Rab10 to Rab10 ratio was observed over time in iPD patients, but not in controls.
• Increased pT73-Rab10 levels correlated with higher Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) scores and lower Montreal Cognitive Assessment (MoCA) scores.

Conclusions:

• Peripheral LRRK2-dependent Rab phosphorylation, measured in urine, shows association with Parkinson disease progression.
• Elevated pT73-Rab10 levels in urinary extracellular vesicles may serve as a biomarker for disease severity and cognitive impairment in iPD.