The LRRK2-RAB axis in regulation of vesicle trafficking and α-synuclein propagation

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Highlights

  • Two major genetic factors of PD, LRRK2 and SNCA, may interact in the pathogenic process.

  • LRRK2 is involved in the regulation of the endolysosomal and autophagic pathways.

  • LRRK2 regulates vesicle trafficking through the interaction with and phosphorylation of RAB proteins.

  • The LRRK2-RAB pathway regulates lysosomal degradation, as well as secretion/propagation, of α-synuclein.

Abstract

LRRK2 and SNCA, the gene for α-synuclein, are the two of the most important genetic factors of Parkinson's disease (PD). A-synuclein is aggregated and accumulated in neurons and glia in PD and considered the pathogenic culprit of the disease. A-synuclein aggregates spread from a few discrete regions of the brain to larger areas as the disease progresses through cell-to-cell propagation mechanism. LRRK2 is involved in the regulation of vesicle trafficking, in particular in the endolysosomal and autophagic pathways. Studies also suggest that LRRK2 might regulate the pathogenic actions of α-synuclein. However, the relationship between these two proteins in the pathogenesis of PD remains elusive. Here, we review the current literature on the pathophysiological function of LRRK2 with an emphasis on its role in the endolysosomal and autophagic pathways. We also propose a potential mechanism by which LRRK2 is involved in the regulation of aggregation and the propagation of α-synuclein.

Abbreviations

AD
Autosomal dominant
AR
Autosomal recessive
COR
C-terminal of ROC
DVL
Disheveled
GSK-3
Glycogen synthase kinase-3
GWAS
Genome-wide association studies
LBs
Lewy bodies
LNs
Lewy neurites
LRRK2
Leucine-rich repeat kinase 2
PD
Parkinson's disease
ROC
Ras of complex proteins

Keywords

Parkinson's disease
LRRK2
α-Synuclein
Vesicle trafficking
Protein aggregation

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