Roles of lysosomotropic agents on LRRK2 activation and Rab10 phosphorylation

Kuwahara, Tomohiro; Funakawa, Kai; Komori, Tadayuki; Sakurai, Maria; Yoshii, Gen; Eguchi, Tomohiro; Fukuda, M.; Iwatsubo, Takeshi

doi:10.1016/j.nbd.2020.105081

Cited by 57 publications

(68 citation statements)

References 67 publications

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“…RAB8ALRRK2 kinase substrate, interacts with LRRK and RAB7L1 in endosomal homeostasis. LRRK2-mediated phosphorylation of RAB8A leads to centrosomal alterations68,78,[80][81][82] RAB10 LRRK2 kinase substrate, involved with LRRK and RAB7L1 in endosomal homeostasis 68,78,80-82 RAB12 LRRK2 kinase substrate 68 RAB32 Directly interacts with LRKK and is linked to SNX6/retromer trafficking at the Golgi 83VPS35 RAB5 Implicated with VPS35, LRRK, and Rab11 in Drosophila synaptic vesicle endocytosis 71 RAB7 Recruits retromer on endosomes via interactions with the Vps sub-complex 85-87 RAB7L1 Indication of functional relationship between LRRK, RAB7L1, and VPS35 72 PINK1 RAB8A/B PINK1-induced phosphorylation alters the ability of RAB8A to interact with its GEF Rabin8 88-90 RAB13 Phosphorylated after PINK1 activation 88PARKIN RAB5Recruited to damaged mitochondria after Parkin-mediated ubiquitination of RABGEF191 …”

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confidence: 99%

Dysfunction of RAB39B‐Mediated Vesicular Trafficking in Lewy Body Diseases

et al. 2021

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Intracellular vesicular trafficking is essential for neuronal development, function, and homeostasis and serves to process, direct, and sort proteins, lipids, and other cargo throughout the cell. This intricate system of membrane trafficking between different compartments is tightly orchestrated by Ras analog in brain (RAB) GTPases and their effectors. Of the 66 members of the RAB family in humans, many have been implicated in neurodegenerative diseases and impairment of their functions contributes to cellular stress, protein aggregation, and death. Critically, RAB39B loss-of-function mutations are known to be associated with X-linked intellectual disability and with rare early-onset Parkinson's disease. Moreover, recent studies have highlighted altered RAB39B expression in idiopathic cases of several Lewy body diseases (LBDs). This review contextualizes the role of RAB proteins in LBDs and highlights the consequences of RAB39B impairment in terms of endosomal trafficking, neurite outgrowth, synaptic maturation, autophagy, as well as alpha-synuclein homeostasis. Additionally, the potential for therapeutic intervention is examined via a discussion of the recent progress towards the development of specific RAB modulators.

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confidence: 99%

Dysfunction of RAB39B‐Mediated Vesicular Trafficking in Lewy Body Diseases

et al. 2021

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“…Recent work has shown that inducing lysosomal damage causes recruitment of LRRK2 to lysosomes, followed by the lysosomal accumulation of phospho-Rab10 (39)(40)(41)(42). Conversely, mitochondrial depolarization causes the mitochondrial accumulation of Rab10 to facilitate mitophagy, and such accumulation is impaired in the context of pathogenic LRRK2 (43).…”

Section: Discussionmentioning

confidence: 99%

LRRK2 causes centrosomal deficits via phosphorylated Rab10 and RILPL1 at centriolar subdistal appendages

Ordóñez

Fernández

Fasiczka

et al. 2021

Preprint

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The Parkinson′s disease-associated LRRK2 kinase phosphorylates multiple Rab GTPases including Rab8 and Rab10, which enhances their binding to RILPL1 and RILPL2. The nascent interaction between phospho-Rab10 and RILPL1 blocks ciliogenesis in vitro and in the intact brain, and interferes with the cohesion of duplicated centrosomes in dividing cells. We show here that various LRRK2 risk variants and all currently described regulators of the LRRK2 signaling pathway converge upon causing centrosomal cohesion deficits. The cohesion deficits do not require the presence of RILPL2 or of other LRRK2 kinase substrates including Rab12, Rab35 and Rab43. Rather, they depend on the RILPL1-mediated centrosomal accumulation of phosphorylated Rab10. RILPL1 localizes to the subdistal appendages of the mother centriole, followed by recruitment of the LRRK2-phosphorylated Rab protein to cause the centrosomal defects. These data reveal a common molecular pathway by which alterations in the LRRK2 kinase activity impact upon centrosome-related events.

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“…These toxicants have been intensively investigated in animal models of PD. LRRK2 mutant protein contributes to multiple pathways and mechanisms, including neuroinflammation [64], endolysosomal and oxidative stress [61,135,136], and mitochondrial dysfunction and clearance [67,137]. Variable penetrance and AAO also suggest multiple hits for disease development [138,139], including predisposing germline gene mutations, acquired somatic gene variants [140], the environmental factors described in Section 2.1, and aging [141].…”

Section: Increased Susceptibility To Synthetic Toxicants In Lrrk2 Animal Modelsmentioning

confidence: 99%

Genetic and Environmental Factors Influence the Pleomorphy of LRRK2 Parkinsonism

Chittoor-Vinod

Nichols

Schüle

2021

IJMS

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Missense mutations in the LRRK2 gene were first identified as a pathogenic cause of Parkinson’s disease (PD) in 2004. Soon thereafter, a founder mutation in LRRK2, p.G2019S (rs34637584), was described, and it is now estimated that there are approximately 100,000 people worldwide carrying this risk variant. While the clinical presentation of LRRK2 parkinsonism has been largely indistinguishable from sporadic PD, disease penetrance and age at onset can be quite variable. In addition, its neuropathological features span a wide range from nigrostriatal loss with Lewy body pathology, lack thereof, or atypical neuropathology, including a large proportion of cases with concomitant Alzheimer’s pathology, hailing LRRK2 parkinsonism as the “Rosetta stone” of parkinsonian disorders, which provides clues to an understanding of the different neuropathological trajectories. These differences may result from interactions between the LRRK2 mutant protein and other proteins or environmental factors that modify LRRK2 function and, thereby, influence pathobiology. This review explores how potential genetic and biochemical modifiers of LRRK2 function may contribute to the onset and clinical presentation of LRRK2 parkinsonism. We review which genetic modifiers of LRRK2 influence clinical symptoms, age at onset, and penetrance, what LRRK2 mutations are associated with pleomorphic LRRK2 neuropathology, and which environmental modifiers can augment LRRK2 mutant pathophysiology. Understanding how LRRK2 function is influenced and modulated by other interactors and environmental factors—either increasing toxicity or providing resilience—will inform targeted therapeutic development in the years to come. This will allow the development of disease-modifying therapies for PD- and LRRK2-related neurodegeneration.

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Roles of lysosomotropic agents on LRRK2 activation and Rab10 phosphorylation

Cited by 57 publications

References 67 publications

Dysfunction of RAB39B‐Mediated Vesicular Trafficking in Lewy Body Diseases

Dysfunction of RAB39B‐Mediated Vesicular Trafficking in Lewy Body Diseases

LRRK2 causes centrosomal deficits via phosphorylated Rab10 and RILPL1 at centriolar subdistal appendages

Genetic and Environmental Factors Influence the Pleomorphy of LRRK2 Parkinsonism

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