LRRK2, GBA and their interaction in the regulation of autophagy: implications on therapeutics in Parkinson's disease

AbstractMutations in leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA) represent two most common genetic causes of Parkinson ’s disease (PD). Both genes are important in the autophagic-lysosomal pathway (ALP), defects of which are associated with α-synuclein (α-syn) accumulation. LRRK2 regulates macroautophagyvia activation of the mitogen activated protein kinase/extracellular signal regulated protein kinase (MAPK/ERK) kinase (MEK) and the calcium-dependent adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathways. Phosphorylation of Rab GTPases by LRRK2 regulates lysosomal homeostasis and endosomal trafficking. Mutant LRRK2 impairs chaperone-mediated autophagy, resulting in α-syn binding and oligomerization on lysosomal membranes. Mutations inGBA reduce glucocerebrosidase (GCase) activity, leading to glucosylceramide accumulation, α-syn aggregation and broad autophagic abnormalities.LRRK2 andGBA influence each other: GCase activity is reduced inLRRK2 mutant cells, and LRRK2 kinase inhibition can alter GCase activity inGBA mutant cells. Clinically,LRRK2 G2019S mutation seems to modify the effects ofGBA mutation, resulting in milder symptoms than those resulting fromGBA mutation alone. However, dual mutation carriers have an increased risk of PD and earlier age of onset compared with single mutation carriers, suggesting an additive deleterious effect on the initiation of PD pathogenic processes. Crosstalk betweenLRRK2 andGBA in PD exists, but...
Source: Translational Neurodegeneration - Category: Neurology Source Type: research