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

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 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.

Language: Английский

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Endosomal protein DENND10/FAM45A integrates extracellular vesicle release with cancer cell migration

BMC Biology, Journal Year: 2024, Volume and Issue: 22(1)

Published: July 10, 2024

Mounting evidence shows that tumor-derived extracellular vesicles (EVs) are critical constituents in the tumor microenvironment. The composition and function of EVs often change during cancer progression. However, it remains less clear how cells modulate their own EV biogenesis to promote development. release is closely linked endolysosome system residing within cell. current study aims decipher role endosomal protein DENND10 Bioinformatics data mining showed expression significantly associated with poor prognosis multiple types up-regulated metastatic breast cell lines. knockout (DENND10-KO) led defective due impaired endolysosomal trafficking. Intriguingly, DENND10-KO exhibited reductions spreading, migration, invasion, potential vivo. These deficiencies motility were compromised cytoskeleton organization. Importantly, wild-type conditioned medium or restored migratory ability cytoskeletal organization cells. Global proteomic profiling revealed depletion a distinct compositional landscape remodeled profiles matrix (ECM) adhesion molecules. Consistently, exogenous application ECM molecules rescued spreading migration In summary, our unveiled as an intrinsic regulator modifies microenvironment through autocrine release, which could be exploited for developing targeted therapies metastasis.

Language: Английский

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Lysosomal uptake of mtDNA mitigates heteroplasmy

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 16, 2024

Mitochondrial DNA is exposed to multiple insults produced by normal cellular function. Upon mtDNA replication stress the mitochondrial genome transfers endosomes where it degraded. Here, using proximity proteomics we found that leads rewiring of proteome, increasing mitochondria association with lysosomal and vesicle-associated proteins, such as GTPase RAB10 retromer. We upon stress, enhances fragmentation relocates from ER lysosomes containing mtDNA. The retromer coordinates expulsion matrix components through mitochondrial-derived vesicles, direct transfer lysosomes. Using a Drosophila model carrying long deletion on (ΔmtDNA), evaluated in vivo role extraction turnover larval epidermis. presence ΔmtDNA elicits activation specific transcriptome profile related counteract damage. Expression component Vps35 sufficient restore homoplasmy defects associated ΔmtDNA. Our data reveal novel regulators involved elimination demonstrate modulation successful mechanism function

Language: Английский

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Mechanisms of lysosomal tubulation and sorting driven by LRRK2

Biochemical Society Transactions, Journal Year: 2024, Volume and Issue: 52(4), P. 1909 - 1919

Published: July 31, 2024

Lysosomes are dynamic cellular structures that adaptively remodel their membrane in response to stimuli, including damage. Lysosomal dysfunction plays a central role the pathobiology of Parkinson's disease (PD). Gain-of-function mutations Leucine-rich repeat kinase 2 (LRRK2) cause familial PD and genetic variations its locus increase risk developing sporadic form disease. We previously uncovered process we term LYTL (LYsosomal Tubulation/sorting driven by LRRK2), wherein membrane-damaged lysosomes generate tubules sorted into mobile vesicles. Subsequently, these vesicles interact with healthy lysosomes. is orchestrated LRRK2 activity, via recruitment phosphorylation subset RAB GTPases. Here, summarize current understanding regulation, as well unknown aspects this process.

Language: Английский

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TMEM55A-mediated PI5P signaling regulates α-cell actin depolymerization and glucagon secretion

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 17, 2024

Diabetes is associated with the dysfunction of glucagon-producing pancreatic islet α-cells, although underlying mechanisms regulating glucagon secretion and α-cell remain unclear. While insulin from β-cells has long been known to be partly controlled by intracellular phospholipid signaling, very little about role phospholipids in secretion. Here we show that TMEM55A, a lipid phosphatase dephosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) phosphatidylinositol-5-phosphate (PI5P), regulates exocytosis TMEM55A knockdown both human mouse α-cells reduces at low glucose, this rescued direct reintroduction PI5P. This does not occur through an effect on Ca 2+ channel activity, but re-modelling cortical F-actin dependent upon activity which occurs response oxidative stress. In summary, reveal novel pathway manipulating PI5P level network.

Language: Английский

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RAB3 phosphorylation by pathogenic LRRK2 impairs trafficking of synaptic vesicle precursors

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 25, 2023

ABSTRACT Gain-of-function mutations in the LRRK2 gene cause Parkinson’s disease (PD), characterized by debilitating motor and non-motor symptoms. Increased phosphorylation of a subset RAB GTPases is implicated PD pathogenesis. We find that increased RAB3A, cardinal synaptic vesicle precursor (SVP) protein, disrupts anterograde axonal transport SVPs iPSC-derived human neurons (iNeurons) expressing hyperactive -p.R1441H. Knockout opposing protein phosphatase 1H ( PPM1H ) iNeurons phenocopies this effect. In these models, compartmental distribution proteins altered; synaptophysin synaptobrevin-2 become sequestered neuronal soma with decreased delivery to presynaptic sites along axon. RAB3A binding adapter MADD, potentially preventing formation RAB3A-MADD-KIF1A/1Bβ complex driving SVP transport. hyperphosphorylation also interactions RAB3GAP RAB-GDI1. Our results reveal mechanism which pathogenic may contribute altered homeostasis associated characteristic cognitive manifestations PD. SUMMARY Dou et al. demonstrate disease-associated decreases trafficking within disrupting regulation RAB3A. Impaired could progression

Language: Английский

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