Abstract
The Parkinson’s disease (PD)-associated kinase Leucine-Rich Repeat Kinase 2 (LRRK2) is a crucial modulator of the autophagy-lysosome pathway, but unclarity exists on the precise mechanics of its role and the direction of this modulation. In particular, LRRK2 is involved in the degradation of pathological alpha-synuclein, with pathogenic mutations precipitating neuropathology in cellular and animal models of PD, and a significant proportion of LRRK2 patients presenting Lewy neuropathology. Defects in autophagic processing and lysosomal degradation of alpha-synuclein have been postulated to underlie its accumulation and onset of neuropathology. Thus, it is critical to obtain a comprehensive knowledge on LRRK2-associated pathology. Here, we investigated a G2019S-LRRK2 recombinant cell line exhibiting accumulation of endogenous, phosphorylated alpha-synuclein. We found that G2019S-LRRK2 leads to accumulation of LC3 and abnormalities in lysosome morphology and proteolytic activity in a kinase-dependent fashion, but independent from constitutively active Rab10. Notably, LRRK2 inhibition was ineffective upon upstream blockade of autophagosome-lysosome fusion events, highlighting this step as critical for alpha-synuclein clearance.
Highlights
Parkinson’s disease (PD) linked to Lrrk[2] gene mutations is clinically indistinguishable from idiopathic PD but with pleomorphic pathology[1]
Since Leucine-Rich Repeat Kinase 2 (LRRK2) modulates degradation of aSyn by autophagy[10,20] and its kinase activity is linked to aSyn neuropathology[29], we reasoned that pS129-aSyn accumulation in our cells could be related to dysfunctional protein degradation and we interrogated the autophagy-lysosome pathway (ALP)
G2019S-LRRK2 alters lysosome morphology and functionality The results presented so far indicate that LC3B accumulates in G2019S-LRRK2 cells, but in the absence of an increase in their production
Summary
Parkinson’s disease (PD) linked to Lrrk[2] gene mutations is clinically indistinguishable from idiopathic PD (iPD) but with pleomorphic pathology[1]. The G2019S mutation is the most common mutation, with an incidence up to 40% in specific populations[2,3], and often presents with alphasynuclein (aSyn) Lewy neuropathology[4], apart from Tau pathology[5]. Leucine-Rich Repeat Kinase 2 (LRRK2) is a large multidomain protein with GTPase and kinase domains in close vicinity[6]. The PD-linked mutations reside in this enzymatic core, with G2019S located in the kinase domain, and increase kinase activity[7]. LRRK2 cellular roles are varied, with stronger consensus on synaptic transmission[8], vesicle trafficking[9] and autophagy[10], which converge in neuronal biology and function[11].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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.
