LRRK2 Kinase Activity Regulates Parkinson’s Disease-Relevant Lipids at the Lysosome

Maloney, Michael T.; Wang, Xiang; Ghosh, Rajarshi; Andrews, Shan V.; Maciuca, Romeo; Masoud, Shababa T.; Caprioli, Richard M.; Chen, John; Chiu, Chi-Lu; Davis, Sonnet S.; Ho, Audrey Cheuk-Nga; Nguyen, Hoang; Propson, Nicholas E.; Reyzer, Michelle L.; Davis, Oliver B.; Deen, Matthew C.; Zhu, Sha; Vocadlo, David J.; Estrada, Anthony A.; Vicente, Javier De; Lewcock, Joseph W.; Arguello, Annie; Suh, Jung Hee; Huntwork‐Rodriguez, Sarah; Henry, Anastasia G.

doi:10.1101/2022.12.19.521070

Cited by 3 publications

(3 citation statements)

References 82 publications

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“…Depletion of LRRK2 and inhibition of LRRK2 kinase activity both enhance lysosomal proteolytic activity and increase the expression of multiple lysosomal hydrolases ( 32 ). Other work has revealed that LRRK2 kinase activity controls PD relevant lipids such as bis(monoacylglycerol)phosphates as well as glycosphingolipids at the lysosome ( 33, 34 ).…”

Section: Introductionmentioning

confidence: 99%

Parkinson’s VPS35[D620N] mutation induces LRRK2 mediated lysosomal association of RILPL1 and TMEM55B

Pal¹,

Taylor²,

Lam³

et al. 2023

Preprint

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The Parkinsons VPS35[D620N] mutation causes lysosome dysfunction enhancing LRRK2 kinase activity. We find the VPS35[D620N] mutation alters expression of ~350 lysosomal proteins and stimulates LRRK2 phosphorylation of Rab proteins at the lysosome. This recruits the phosphoRab effector protein RILPL1 to the lysosome where it binds to the lysosomal integral membrane protein TMEM55B. We identify highly conserved regions of RILPL1 and TMEM55B that interact and design mutations that block binding. In mouse fibroblasts, brain, and lung, we demonstrate that the VPS35 [D620N] mutation reduces RILPL1 levels, in a manner reversed by LRRK2 inhibition. Knock-out of RILPL1 enhances phosphorylation of Rab substrates and knock-out of TMEM55B increases RILPL1 levels. The lysosomotropic agent LLOMe, also induced LRRK2 kinase mediated association of RILPL1 to the lysosome, but to a lower extent than the D620N mutation. Our study uncovers a pathway through which dysfunctional lysosomes resulting from the VPS35[D620N] mutation recruit and activate LRRK2 on the lysosomal surface, driving assembly of the RILPL1-TMEM55B complex.

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Section: Introductionmentioning

confidence: 99%

Parkinson’s VPS35[D620N] mutation induces LRRK2 mediated lysosomal association of RILPL1 and TMEM55B

Pal¹,

Taylor²,

Lam³

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…It is well-established that pathogenic LRRK2 mutations cause kinase hyperactivity [ 18 ], and studies suggest that these mutations are associated with lysosomal swelling and dysfunction [ 19 , 20 ] A specific mechanism linking kinase hyperactivity with this cellular phenotype is suggested by molecular screens showing that LRRK2's primary function is to phosphorylate many of the family of Rab proteins [ 21 ], which are GTPases that act as effectors in membrane trafficking [ 22 ]. Rab8 and Rab10 are the main Rabs hyperphosphorylated by LRRK2 mutations [ 18 ], and both Rabs are recruited to damaged lysosomes [ 23 , 24 ].…”

Section: Autosomal-dominant Parkinson's Disease and The Endo-lysosoma...mentioning

confidence: 99%

Retromer-dependent lysosomal stress in Parkinson's disease

Alessi,

Cullen,

Cookson

et al. 2024

Phil. Trans. R. Soc. B

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While causative mutations in complex disorders are rare, they can be used to extract a biological pathway whose pathogenicity can generalize to common forms of the disease. Here we begin by relying on the biological consequences of mutations in LRRK2 and VPS35, genetic causes of autosomal-dominant Parkinson's disease, to hypothesize that ‘Retromer-dependent lysosomal stress’ represents a pathway that can generalize to idiopathic Parkinson's disease. Next, we outline a series of studies that can test this hypothesis, including the development of biomarkers of pathway dysfunction. If validated, the hypothesis can suggest a unified mechanism of disease and might inform future diagnostic and therapeutic investigations. This article is part of a discussion meeting issue ‘Understanding the endo-lysosomal network in neurodegeneration’.

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“…Depletion of LRRK2 and inhibition of LRRK2 kinase activity both enhance lysosomal proteolytic activity and increase the expression of multiple lysosomal hydrolases ( 33 ). Other work has revealed that LRRK2 kinase activity controls PD relevant lipids such as bis(monoacylglycerol)phosphates as well as glycosphingolipids at the lysosome ( 34 , 35 ).…”

Section: Introductionmentioning

confidence: 99%

Parkinson’s VPS35[D620N] mutation induces LRRK2-mediated lysosomal association of RILPL1 and TMEM55B

Pal,

Taylor,

Lam

et al. 2023

Sci. Adv.

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We demonstrate that the Parkinson’s VPS35[D620N] mutation alters the expression of ~220 lysosomal proteins and stimulates recruitment and phosphorylation of Rab proteins at the lysosome. This recruits the phospho-Rab effector protein RILPL1 to the lysosome where it binds to the lysosomal integral membrane protein TMEM55B. We identify highly conserved regions of RILPL1 and TMEM55B that interact and design mutations that block binding. In mouse fibroblasts, brain, and lung, we demonstrate that the VPS35[D620N] mutation reduces RILPL1 levels, in a manner reversed by LRRK2 inhibition and proteasome inhibitors. Knockout of RILPL1 enhances phosphorylation of Rab substrates, and knockout of TMEM55B increases RILPL1 levels. The lysosomotropic agent LLOMe also induced LRRK2 kinase–mediated association of RILPL1 to the lysosome, but to a lower extent than the D620N mutation. Our study uncovers a pathway through which dysfunctional lysosomes resulting from the VPS35[D620N] mutation recruit and activate LRRK2 on the lysosomal surface, driving assembly of the RILPL1-TMEM55B complex.

show abstract

LRRK2 Kinase Activity Regulates Parkinson’s Disease-Relevant Lipids at the Lysosome

Cited by 3 publications

References 82 publications

Parkinson’s VPS35[D620N] mutation induces LRRK2 mediated lysosomal association of RILPL1 and TMEM55B

Parkinson’s VPS35[D620N] mutation induces LRRK2 mediated lysosomal association of RILPL1 and TMEM55B

Retromer-dependent lysosomal stress in Parkinson's disease

Parkinson’s VPS35[D620N] mutation induces LRRK2-mediated lysosomal association of RILPL1 and TMEM55B

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