The Cell Biology of LRRK2 in Parkinson's Disease

Usmani, Ahsan; Shavarebi, Farbod; Hiniker, Annie

doi:10.1128/mcb.00660-20

Cited by 52 publications

(40 citation statements)

References 141 publications

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“…However, the role of GAK in the autophagy pathway has not been elucidated. Mutations in LRRK2 cause inherited Pd, and common variants around LRRK2 are risk factors for sporadic PD (67)(68)(69)(70). Genome-wide association studies have identified an SNP in GAK as a risk factor for sporadic Pd (39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

Targeted disruption of GAK stagnates autophagic flux by disturbing lysosomal dynamics

et al. 2021

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The autophagy-lysosome system allows cells to adapt to environmental changes by regulating the degradation and recycling of cellular components, and to maintain homeostasis by removing aggregated proteins and defective organelles. cyclin G-associated kinase (GAK) is involved in the regulation of clathrin-dependent endocytosis and cell cycle progression. In addition, a single nucleotide polymorphism at the GAK locus has been reported as a risk factor for Parkinson's disease. However, the roles of GAK in the autophagy-lysosome system are not completely understood, thus the present study aimed to clarify this. In the present study, under genetic disruption or chemical inhibition of GAK, analyzing autophagic flux and observing morphological changes of autophagosomes and autolysosomes revealed that GAK controlled lysosomal dynamics via actomyosin regulation, resulting in a steady progression of autophagy. GAK knockout (KO) in A549 cells impaired autophagosome-lysosome fusion and autophagic lysosome reformation, which resulted in the accumulation of enlarged autophagosomes and autolysosomes during prolonged starvation. The stagnation of autophagic flux accompanied by these phenomena was also observed with the addition of a GAK inhibitor. Furthermore, the addition of Rho-associated protein kinase (ROcK) inhibitor or ROcK1 knockdown mitigated GAK KO-mediated effects. The results suggested a vital role of GAK in controlling lysosomal dynamics via maintaining lysosomal homeostasis during autophagy.

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Section: Discussionmentioning

confidence: 99%

Targeted disruption of GAK stagnates autophagic flux by disturbing lysosomal dynamics

et al. 2021

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“…Understanding how LRRK2 functions and what goes wrong in disease-causing mutations will inform the rational design of specific LRRK2 inhibitors. Indeed, much effort has been directed at exploring the structure-function relationships in LRRK2 to gain a mechanistic understanding and guide the rational drug discovery (Usmani et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Structural basis of human LRRK2 membrane recruitment and activation

Zhu

Tonelli

Alessi

et al. 2022

Preprint

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SummaryMutations in LRRK2 are the most common genetic cause of late-onset Parkinson’s disease (PD). LRRK2 encodes the leucine-rich repeat kinase 2 (LRRK2), whose kinase activity is regulated by Rab29, a membrane-anchored GTPase. However, molecular mechanisms underlying Rab29-dependent recruitment and activation of LRRK2 remain unclear. Here we report cryo-EM structures of LRRK2–Rab29 complexes in three oligomeric states, illustrating snapshots of key steps during LRRK2 membrane recruitment and activation. Rab29 binds to the ARM domain of LRRK2, and disruption at the interface abrogates LRRK2 kinase activity. Activation of LRRK2 is underpinned by the formation of an unexpected Rab29-induced super-assembly containing two central kinase-active and two peripheral kinase-inactive LRRK2 protomers. Central protomers undergo pronounced oligomerization-associated rearrangements and adopt an active conformation. Our work reveals the structural mechanism for LRRK2’s spatial regulation controlled by Rab GTPases, provides mechanistic insights into pathogenic mutations and identifies new opportunities to design LRRK2 inhibitors for PD treatment.

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“…Literature citations and REVEL scores [38] (http://database.liulab.science/dbNSFP) for each of the selected variants, as well as evolutionary conservation scores for each variant amino acid determined using the Consurf database (https://consurf.tau.ac.il/) [43], are tabulated in STable 1. The selected variants are located within the following domains: ARM (18), ANK (9), LRR (12), ROC (15), CORA (6), CORB (8), kinase (9) and WD40 (14) domains, as well as between the boundaries of the ANK and LRR (5), and LRR and ROC domains (2) (Fig 1A).…”

Section: Resultsmentioning

confidence: 99%

Impact of 100 LRRK2 variants linked to Parkinson’s Disease on kinase activity and microtubule binding

Kalogeropulou

Purlyte

Tonelli

et al. 2022

Preprint

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Mutations enhancing the kinase activity of LRRK2 cause Parkinson's disease (PD) and therapies that reduce LRRK2 kinase activity are being tested in clinical trials. Numerous rare variants of unknown clinical significance have been reported, but how the vast majority impact on LRRK2 function is unknown. Here, we investigate 98 LRRK2 variants linked to PD, including previously described pathogenic mutations, and identify 22 variants that robustly stimulate LRRK2 kinase activity. These include variants within the N-terminal non-catalytic regions [ARM (E334K, A419V), ANK (R767H), LRR (R1067Q, R1325Q)] as well as variants residing within the GTPase domain, predicted to destabilise the ROC:CORB interface [ROC (A1442P, V1447M), CORB (S1761R, L1795F)] and CORB:CORB dimer interface [CORB (R1728H/L)]. Most activating variants decrease LRRK2 biomarker site phosphorylation (pSer910/pSer935), consistent with the notion that the active kinase conformation blocks their phosphorylation. We find that the R1628P variant that has been linked to PD does not stimulate LRRK2 activity. We observe that the impact of variants on kinase activity is best evaluated by deploying a cellular assay of LRRK2-dependent Rab10 substrate phosphorylation at Thr73 compared to an in vitro kinase assay, as only a minority of activating variants enhance the activity of immunoprecipitated LRRK2, comprising the CORB (Y1699C, R1728H, S1761R) and kinase (G2019S, I2020T, T2031S) variants. Twelve variants including some that activated LRRK2, suppressed microtubule association in the presence of a Type 1 kinase inhibitor [ARM (M712V), LRR (R1320S), ROC (A1442P, K1468E, S1508R), CORA (A1589S), CORB (Y1699C, R1728H/L) and WD40 (R2143M, S2350I, G2385R)]. Our findings will aid in understanding the impact of these variants on LRRK2 kinase activation, stimulate work to reveal mechanisms by which variants impact biology, and provide rationale for variant carrier inclusion or exclusion in ongoing and future LRRK2 clinical trials.

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The Cell Biology of LRRK2 in Parkinson's Disease

Cited by 52 publications

References 141 publications

Targeted disruption of GAK stagnates autophagic flux by disturbing lysosomal dynamics

Targeted disruption of GAK stagnates autophagic flux by disturbing lysosomal dynamics

Structural basis of human LRRK2 membrane recruitment and activation

Impact of 100 LRRK2 variants linked to Parkinson’s Disease on kinase activity and microtubule binding

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