Membrane remodeling properties of the Parkinson’s disease protein LRRK2

Wang, Xinbo; Wu, Yumei; Cai, Shujun; Ge, Jinghua; Shao, Lin; Camilli, Pietro De

doi:10.1101/2022.08.10.503505

Cited by 8 publications

(6 citation statements)

References 55 publications

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“…It remains to be determined whether GABARAP acts in parallel with any of these Rabs to ensure that LRRK2 is recruited to and activated at the correct intracellular membranes. It was also very recently discovered that LRRK2 can assemble into helical polymers on membranes that are enriched in acidic lipid head groups (Wang et al, 2023b). Such LRRK2-membrane interactions could also act together with GABARAP to specify sites of LRRK2 activation.…”

Section: Discussionmentioning

confidence: 99%

A STING-CASM-GABARAP Pathway Activates LRRK2 at Lysosomes

Bentley-DeSousa,

Roczniak-Ferguson,

Ferguson

2023

Preprint

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Mutations that increase LRRK2 kinase activity have been linked to Parkinson’s disease and Crohn’s disease. LRRK2 is also activated by lysosome damage evoked by chemical and pathogenic stimuli. However, the endogenous cellular mechanisms that control LRRK2 kinase activity are not well understood. In this study, we identify signaling through Stimulator of Interferon Genes (STING) as an upstream activator of LRRK2. This LRRK2 activation occurs via the Conjugation of ATG8 to Single Membranes (CASM) pathway. We furthermore establish that multiple chemical stimuli that perturb lysosomal homeostasis also converge on CASM to activate LRRK2. Although CASM mediates the lipidation of multiple ATG8 protein family members, LRRK2 lysosome recruitment and kinase activation is highly dependent on an interaction with the GABARAP member of this family. Collectively these results define a pathway that integrates multiple stimuli at lysosomes to control the kinase activity of LRRK2. Aberrant activation this pathway may be of relevance in both Parkinson’s and Crohn’s diseases.

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Section: Discussionmentioning

confidence: 99%

A STING-CASM-GABARAP Pathway Activates LRRK2 at Lysosomes

Bentley-DeSousa,

Roczniak-Ferguson,

Ferguson

2023

Preprint

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“…Additionally, phosphorylation of Rab GTPases by LRRK2 could change the composition of lysosomes by regulating intracellular membrane traffic and thus affect TFE3 lysosome recruitment and phosphorylation 14 . Recently described membrane remodelling properties of LRRK2 might also play a role 63 . Alternatively, defects in lysosome membrane integrity following LRRK2 depletion or inhibition could result in the release of lysosomal calcium and calcineurin-mediated dephosphorylation of TFE3 proteins 15,[64][65][66] .…”

Section: Discussionmentioning

confidence: 99%

LRRK2 Suppresses Lysosome Degradative Activity in Macrophages and Microglia Through MiT-TFE Transcription Factor Inhibition

Yadavalli

Ferguson

2022

Preprint

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Variants in leucine rich repeat kinase 2 (LRRK2) that increase kinase activity confer risk for sporadic and familial forms of Parkinson's disease. However, LRRK2-dependent cellular processes responsible for disease risk remain uncertain. Here we show that LRRK2 negatively regulates lysosome degradative activity in macrophages and microglia via a transcriptional mechanism. Depletion of LRRK2 and inhibition of LRRK2 kinase activity both enhance lysosomal proteolytic activity and increase the expression of multiple lysosomal hydrolases. Conversely, the kinase hyperactive LRRK2 G2019S Parkinson's disease mutant suppresses lysosomal degradative activity and gene expression. We identified transcription factor E3 (TFE3) as a mediator of LRRK2-dependent control of lysosomal gene expression. LRRK2 negatively regulates both the abundance and nuclear localization of TFE3 and LRRK2-dependent changes in lysosome protein expression require TFE3. These discoveries define a mechanism for LRRK2-dependent control of lysosomes and support a model wherein LRRK2 hyperactivity increases Parkinson's disease risk by suppressing lysosome degradative activity.

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“…Datasets and Codes data have been deposited in zenodo https://doi.org/10.5281/zenodo.8335319 ( 51 ). All other data are included in the manuscript and/or supporting information .…”

Section: Data Materials and Software Availabilitymentioning

confidence: 99%

Membrane remodeling properties of the Parkinson’s disease protein LRRK2

Wang,

Espadas,

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in Leucine-rich repeat kinase 2 (LRRK2) are responsible for late-onset autosomal dominant Parkinson’s disease. LRRK2 has been implicated in a wide range of physiological processes including membrane repair in the endolysosomal system. Here, using cell-free systems, we report that purified LRRK2 directly binds acidic lipid bilayers with a preference for highly curved bilayers. While this binding is nucleotide independent, LRRK2 can also deform low-curvature liposomes into narrow tubules in a guanylnucleotide-dependent but Adenosine 5′-triphosphate-independent way. Moreover, assembly of LRRK2 into scaffolds at the surface of lipid tubules can constrict them. We suggest that an interplay between the membrane remodeling and signaling properties of LRRK2 may be key to its physiological function. LRRK2, via its kinase activity, may achieve its signaling role at sites where membrane remodeling occurs.

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Membrane remodeling properties of the Parkinson’s disease protein LRRK2

Cited by 8 publications

References 55 publications

A STING-CASM-GABARAP Pathway Activates LRRK2 at Lysosomes

A STING-CASM-GABARAP Pathway Activates LRRK2 at Lysosomes

LRRK2 Suppresses Lysosome Degradative Activity in Macrophages and Microglia Through MiT-TFE Transcription Factor Inhibition

Membrane remodeling properties of the Parkinson’s disease protein LRRK2

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