The Multifaceted Role of LRRK2 in Parkinson’s Disease

Brain Sciences, Год журнала: 2025, Номер 15(4), С. 407 - 407

Опубликована: Апрель 17, 2025

Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein intricately involved in the pathogeneses of various neurodegenerative diseases, particularly Parkinson's disease (PD). LRRK2 plays pivotal role mitochondrial function and cellular senescence by regulating key processes such as autophagy, oxidative stress, aggregation. also associated with ciliogenesis neuronal development. In addition, has been implicated putative mediator neuroinflammation via promoting reactivation microglia influencing cytokine production, factor that may have therapeutic implications. Furthermore, mutations found to impact production neurotrophic factors astrocytes, star-shaped glial cells central nervous system, thereby affecting health contributing pathology diseases like PD. The multifaceted roles senescence, interaction LRS, neuroinflammation, maintenance mitochondria, astrocyte highlight its significance target for disorders.

Язык: Английский

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Mitophagy in Neurons: Mechanisms Regulating Mitochondrial Turnover and Neuronal Homeostasis

Journal of Molecular Biology, Год журнала: 2025, Номер unknown, С. 169161 - 169161

Опубликована: Апрель 1, 2025

Mitochondrial quality control is instrumental in regulating neuronal health and survival. The receptor-mediated clearance of damaged mitochondria by autophagy, known as mitophagy, plays a key role controlling mitochondrial homeostasis. Mutations genes that regulate mitophagy are causative for familial forms neurological disorders including Parkinson's disease (PD) Amyotrophic lateral sclerosis(ALS). PINK1/Parkin-dependent the best studied pathway, while more recent work has brought to light additional mechanisms operate either parallel or independent PINK1/Parkin mitophagy. Here, we discuss our current understanding operating neurons govern We also summarize progress links between mitophagic dysfunction neurodegeneration highlight potential therapeutic interventions maintain function.

Язык: Английский

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Roles of LRRK2 and its orthologs in protecting against neurodegeneration and neurodevelopmental defects

Frontiers in Cell and Developmental Biology, Год журнала: 2025, Номер 13

Опубликована: Апрель 30, 2025

In humans, variants in the LRRK2 gene are most prevalent risk factors for Parkinson's disease (PD). Whereas studies model organisms have long indicated that orthologs of wild-type LRRK proteins protect against neurodegeneration, newer findings indicate they also neurodevelopmental defects. This normal role can be disrupted by either gain-of-function (GOF) or loss-of-function (LOF) mutations, leading to neurodegeneration and Here, we review roles their these processes, with a focus on autophagy as common factor may mediate both roles. We highlight potential experiments vertebrate invertebrate systems synergistically inform our understanding protecting neurological disorders.

Язык: Английский

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Protocol for live imaging of axonal transport in iPSC-derived iNeurons

STAR Protocols, Год журнала: 2025, Номер 6(1), С. 103556 - 103556

Опубликована: Янв. 12, 2025

Язык: Английский

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Axonal transport of autophagosomes is regulated by dynein activators JIP3/JIP4 and ARF/RAB GTPases

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Янв. 29, 2023

Neuronal autophagosomes, "self-eating" degradative organelles, form at presynaptic sites in the distal axon and are transported to soma recycle their cargo. During transit, autophagic vacuoles (AVs) mature through fusion with lysosomes acquire enzymes necessary breakdown AV transport is driven primarily by microtubule motor cytoplasmic dynein concert dynactin a series of activating adaptors that change depending on organelle maturation state. The AVs regulated scaffolding proteins JIP3 JIP4, both which activate motility vitro. also ARF6 GTP-dependent fashion. While GTP-bound promotes formation JIP3/4-dynein-dynactin complex, RAB10 competes activity this complex increasing kinesin recruitment axonal lysosomes. These interactions highlight coordination motors regulating neurons.

Язык: Английский

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Driving autophagy – the role of molecular motors

Journal of Cell Science, Год журнала: 2024, Номер 137(3)

Опубликована: Фев. 1, 2024

ABSTRACT Most of the vesicular transport pathways inside cell are facilitated by molecular motors that move along cytoskeletal networks. Autophagy is a well-explored catabolic pathway initiated formation an isolation membrane known as phagophore, which expands to form double-membraned structure captures its cargo and eventually moves towards lysosomes for fusion. Molecular elements have been suggested participate at different stages process autophagic vesicles tracks. Dynein kinesins govern autophagosome trafficking on microtubules through sequential recruitment their effector proteins, post-translational modifications interactions with LC3-interacting regions (LIRs). In contrast, myosins actin-based in various flux, well selective autophagy pathways. However, several outstanding questions remain regard how dominance particular motor protein over another controlled, mechanisms underlie specific disease variants proteins. this Review, we aim provide overview role highlight dysregulation diseases, such neurodegenerative disorders pathogenic infections, ageing.

Язык: Английский

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Opposing actions of JIP4 and RILPL1 provide antagonistic motor force to dynamically regulate membrane reformation during lysosomal tubulation/sorting driven by LRRK2

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 3, 2024

ABSTRACT Lysosomes are dynamic cellular structures that adaptively remodel their membrane in response to stimuli, including damage. We previously uncovered a process we term LYTL (LYsosomal Tubulation/sorting driven by Leucine-Rich Repeat Kinase 2 [LRRK2]), wherein damaged lysosomes generate tubules sorted into mobile vesicles. is orchestrated the Parkinson’s disease-associated kinase LRRK2 recruits motor adaptor protein and RHD family member JIP4 via phosphorylated RAB proteins. To identify new players involved LYTL, performed unbiased proteomics on isolated after inhibition. Our results demonstrate there recruitment of RILPL1 ruptured activity promote phosphorylation proteins at lysosomal surface. RILPL1, which also family, enhances clustering LRRK2-positive perinuclear area causes retraction tubules, contrast promotes tubule extension. Mechanistically, binds p150 Glued , dynactin subunit, facilitating transport minus end microtubules. Further characterization tubulation revealed move along tyrosinated microtubules, with tubulin tyrosination proving essential for elongation. In summary, our findings emphasize regulation two distinct pRAB effectors, serving as opposing proteins: JIP4, promoting kinesin, through dynein/dynactin. infer processes metastable deformation facilitates events.

Язык: Английский

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Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 11, 2024

ABSTRACT Mutations in LRRK2 and PINK1 are associated with familial Parkinson’s disease (PD). phosphorylates Rab GTPases within the Switch II domain whilst directly Parkin ubiquitin indirectly induces phosphorylation of a subset GTPases. Herein we have crossed [R1441C] mutant knock-in mice knock-out (KO) report that loss does not impact endogenous LRRK2-mediated nor do see significant effect on PINK1-mediated phosphorylation. In addition, observe pool Rab-specific, PPM1H phosphatase, is transcriptionally up-regulated recruited to damaged mitochondria, independent or activity. Parallel signalling pathways supported by assessment motor behavioural studies show no evidence genetic interaction mouse lines. Previously showed cilia R1441C herein KO exhibit ciliogenesis defect striatal cholinergic interneurons astrocytes interferes Hedgehog induction glial derived-neurotrophic factor (GDNF) transcription. This exacerbated double mice. Overall, our analysis indicates activation and/or function along parallel impair ciliogenesis, suggesting convergent mechanism towards PD. Our data suggests reversal defects downstream offers common therapeutic strategy for PD patients whereas inhibitors currently clinical trials unlikely benefit patients.

Язык: Английский

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RAB12-LRRK2 complex suppresses primary ciliogenesis and regulates centrosome homeostasis in astrocytes

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Сен. 29, 2024

Язык: Английский

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RAB12-LRRK2 Complex Suppresses Primary Ciliogenesis and Regulates Centrosome Homeostasis in Astrocytes

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 19, 2024

Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of RAB GTPases, and the phosphorylation levels are elevated by Parkinson's disease (PD)-linked mutations LRRK2. However, precise function specific GTPase targeted LRRK2 signaling in brain remains to be elucidated. Here, we identify RAB12 as robust substrate mouse brains through phosphoproteomics profiling solve structure RAB12-LRRK2 protein complex Cryo-EM analysis. Mechanistically, cooperates with inhibit primary ciliogenesis regulate centrosome homeostasis astrocytes enhancing RAB10 recruiting Rab interacting lysosomal like 1 (RILPL1), while functions require direct interaction activity. Furthermore, ciliary deficits alteration caused PD-linked LRRK2-G2019S mutation prevented deletion

Язык: Английский

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