Abstract
Mutations 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 macroautophagy via 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 in GBA reduce glucocerebrosidase (GCase) activity, leading to glucosylceramide accumulation, α-syn aggregation and broad autophagic abnormalities. LRRK2 and GBA influence each other: GCase activity is reduced in LRRK2 mutant cells, and LRRK2 kinase inhibition can alter GCase activity in GBA mutant cells. Clinically, LRRK2 G2019S mutation seems to modify the effects of GBA mutation, resulting in milder symptoms than those resulting from GBA 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 between LRRK2 and GBA in PD exists, but its exact mechanism is unclear. Drugs that inhibit LRRK2 kinase or activate GCase are showing efficacy in pre-clinical models. Since LRRK2 kinase and GCase activities are also altered in idiopathic PD (iPD), it remains to be seen if these drugs will be useful in disease modification of iPD.
Highlights
Autophagy is a degradation process to remove proteins and dysfunctional organelles from cells to prevent subsequent toxicity and cell death
Conclusions and future directions The identification of leucine-rich repeat kinase 2 (LRRK2) and GBA mutations in familial and sporadic Parkinson’s disease (PD) has led to major advancement in the past 10 years in our understanding of the regulation of autophagic-lysosomal pathway (ALP)
The lysosome has emerged to be a critical player in maintaining α-syn homeostasis and is where the effects of LRRK2 and GBA mutations converge
Summary
Autophagy is a degradation process to remove proteins and dysfunctional organelles from cells to prevent subsequent toxicity and cell death. Neuroblastoma cells with GBA knockout have increased accumulation of lysosomal substrates p62 and polyubiquinated proteins, increased Lysotracker staining indicative of reduced breakdown of acidic organelles, increased abnormal accumulation of enlarged autophagic vesicles and increased insoluble α-syn as well as α-syn release, further illustrating the critical role of GCase activity in maintaining normal lysosomal function and α-syn homeostasis [68].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
