LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis

Eguchi, Tomohiro; Kuwahara, Tomohiro; Sakurai, Maria; Komori, Tadayuki; Fujimoto, Tetta; Ito, Genta; Yoshimura, Satoshi; Harada, Akira; Fukuda, Mitsunori; Koike, Masato; Iwatsubo, Takeshi

doi:10.1073/pnas.1812196115

Cited by 229 publications

(321 citation statements)

References 57 publications

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“…Increased LRRK2 kinase activity mediated elevation of exocytosis may also be relevant for cell‐to‐cell transfer of misfolded α‐synuclein (Lin et al ; Bae et al ; Schapansky et al ). LRRK2 can be selectively recruited to overloaded lysosomes and divert undegraded materials out of the kidney cells, along with secretion of α‐synuclein from endosomes (Eguchi et al ). Studies also demonstrate heightened uptake of α‐synuclein fibrils through endocytosis in the presence of pathogenic LRRK2 (Bae et al ).…”

Section: E‐l System; a Key Target Of Key Pd‐associated Proteins?mentioning

confidence: 99%

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Role of the endolysosomal system in Parkinson’s disease

Vidyadhara

Lee

Chandra

2019

Journal of Neurochemistry

104

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Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, affecting 1–1.5% of the total population. While progress has been made in understanding the neurodegenerative mechanisms that lead to cell death in late stages of PD, mechanisms for early, causal pathogenic events are still elusive. Recent developments in PD genetics increasingly point at endolysosomal (E‐L) system dysfunction as the early pathomechanism and key pathway affected in PD. Clathrin‐mediated synaptic endocytosis, an integral part of the neuronal E‐L system, is probably the main early target as evident in auxilin, RME‐8, and synaptojanin‐1 mutations that cause PD. Autophagy, another important pathway in the E‐L system, is crucial in maintaining proteostasis and a healthy mitochondrial pool, especially in neurons considering their inability to divide and requirement to function an entire life‐time. PINK1 and Parkin mutations severely perturb autophagy of dysfunctional mitochondria (mitophagy), both in the cell body and synaptic terminals of dopaminergic neurons, leading to PD. Endolysosomal sorting and trafficking is also crucial, which is complex in multi‐compartmentalized neurons. VPS35 and VPS13C mutations noted in PD target these mechanisms. Mutations in GBA comprise the most common risk factor for PD and initiate pathology by compromising lysosomal function. This is also the case for ATP13A2 mutations. Interestingly, α‐synuclein and LRRK2, key proteins involved in PD, function in different steps of the E‐L pathway and target their components to induce disease pathogenesis. In this review, we discuss these E‐L system genes that are linked to PD and how their dysfunction results in PD pathogenesis. This article is part of the Special Issue “Synuclein”.

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Section: E‐l System; a Key Target Of Key Pd‐associated Proteins?mentioning

confidence: 99%

“…LRRK2 regulates lysosomal protein trafficking and morphology (Kuwahara et al 2016;Eguchi et al 2018). In LRRK2 mutants, perinuclear lysosomal clustering was noted, mediated by increased phosphorylation of RAB7 (Hockey et al 2015).…”

Section: Lrrk2mentioning

confidence: 99%

Role of the endolysosomal system in Parkinson’s disease

Vidyadhara

Lee

Chandra

2019

Journal of Neurochemistry

104

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“…Recent studies suggest that the phosphorylation of Rab10 is dependent on the stable membrane association of LRRK2 20 . Analysis of endogenous LRRK2 subcellular localization in macrophages shows a more diffusive distribution through the cytoplasm in typical non-stimulated cells in culture, with LRRK2 localization apparently unaffected by kinase inhibition in these cells ( Figure 5A).…”

Section: Lrrk2 Transiently Interacts With Rab10mentioning

confidence: 99%

LRRK2 and Rab10 Coordinate Macropinocytosis to Mediate Immunological Responses in Phagocytes

Zhao

et al. 2020

Preprint

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Genetic variation in LRRK2 associates with susceptibility to Parkinson's disease, Crohn's disease, and mycobacteria infection, with high expression of LRRK2, and the LRRK2 kinase substrate Rab10, in phagocytic cells in the immune system. In mouse and human primary monocyte-derived macrophages, dendritic cells, and microglia-like cells, we find that Rab10 specifically regulates a specialized form of endocytosis known as macropinocytosis, without affecting phagocytosis or clathrin-mediated endocytosis. LRRK2 phosphorylates cytoplasmic PI(3,4,5)P 3 -positive GTP-Rab10 early macropinosomes, before EEA1 and Rab5 recruitment occurs. Macropinosome cargo in macrophages includes CCR5, CD11b, and MHCII, with LRRK2-phosphorylation of Rab10 potently blocking EHBP1L1-mediated recycling tubules and cargo turnover. EHBP1L1 over-expression competitively inhibits LRRK2-phosphorylation of Rab10, mimicking the effects of LRRK2 kinase inhibition in promoting cargo recycling. Both Rab10 knockdown and LRRK2 kinase inhibition potently suppresses the maturation of macropinosome-derived CCR5-loaded signaling endosomes important for CCL5-induced AKT-activation and chemotaxis. These data support a novel axis in the endolysosomal system whereby LRRK2-mediated Rab10 phosphorylation stalls vesicle fast-recycling to promote PI3K-AKT signal transduction.

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“…However, the mechanistic basis by which LRRK2 affects lysosome function is unclear. Additionally, because LRRK2 can be localized to a wide range of other membrane-bound structures in cells (8), (21,22), whether LRRK2-mediated lysosomal defects are primary events or secondary effects driven by toxicity to other cellular components is uncertain.…”

Section: Introductionmentioning

confidence: 99%

LRRK2 mediates tubulation and vesicle sorting from membrane damaged lysosomes

Bonet-Ponce

Beilina

et al. 2020

Preprint

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Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are a cause of familial and sporadic Parkinson's disease (PD). Nonetheless, the biological functions of LRRK2 remain incompletely understood. Here, we observed that LRRK2 is recruited to lysosomes that have a ruptured membrane. Using unbiased proteomics, we observed that LRRK2 is able to recruit the motor adaptor protein JIP4 to permeabilized lysosomes in a kinase-dependent manner through the phosphorylation of RAB35 and RAB10.Super-resolution live cell imaging microscopy and FIB-SEM revealed that once at the lysosomal membrane, JIP4 promotes the formation of LAMP1-negative lysosomal tubules that release membranous content from ruptured lysosomes. Released vesicular structures are able to interact with other lysosomes. Thus, we described a new process that uses lysosomal tubulation to release vesicular structures from permeabilized lysosomes. LRRK2 orchestrates this process that we name LYTL (LYsosomal Tubulation/sorting driven by LRRK2) that, given the central role of the lysosome in PD, is likely to be disease relevant.

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LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis

Cited by 229 publications

References 57 publications

Role of the endolysosomal system in Parkinson’s disease

Role of the endolysosomal system in Parkinson’s disease

LRRK2 and Rab10 Coordinate Macropinocytosis to Mediate Immunological Responses in Phagocytes

LRRK2 mediates tubulation and vesicle sorting from membrane damaged lysosomes

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