Mechanisms of lysosomal tubulation and sorting driven by LRRK2

Biochemical Society Transactions, Год журнала: 2024, Номер 52(4), С. 1909 - 1919

Опубликована: Июль 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.

Язык: Английский

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The Rab7-Epg5 and Rab39-ema modules cooperately position autophagosomes for efficient lysosomal fusions

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

Опубликована: Авг. 19, 2024

Abstract Macroautophagy, a major self-degradation pathway in eukaryotic cells, utilizes autophagosomes to transport self-material lysosomes for degradation. While microtubular is crucial the proper function of autophagy, exact roles factors responsible positioning remain incompletely understood. In this study, we performed loss-of-function genetic screen targeting genes potentially involved motility. A background that blocks autophagosome-lysosome fusions was used accurately analyze autophagosome positioning. We discovered pre-fusion move towards non-centrosomal microtubule organizing center (ncMTOC) Drosophila fat which requires dynein-dynactin complex. This process regulated by small GTPases Rab7 and Rab39 together with their adaptors: Epg5 ema, respectively. The dynein-dependent movement vesicles toward nucleus/ncMTOC essential efficient autophagosomal subsequent Remarkably, altering balance kinesin dynein motors changes direction movement, indicating competitive relationship where normally dynein-mediated prevails. Since were positioned similarly autophagosomes, it indicates converge at ncMTOC, increases efficiency vesicle fusions.

Язык: Английский

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Autophagic enhancer rescues Tau accumulation in a stem cell model of frontotemporal dementia

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

Опубликована: Окт. 2, 2024

Abstract Tau degradation is disrupted in neurodegenerative tauopathies, such as frontotemporal dementia (FTD), which may contribute to aggregation. The prevailing hypothesis has been that stymied due an imbalance proteostasis occurs with age. Here, we used Airyscan super resolution imaging illustrate a pathogenic FTD mutation the MAPT gene, encodes Tau, sufficient alter multiple steps of autophagy lysosomal pathway and impair degradation. We discovered lysosomes clogged both phosphorylated stalled lysosome motility, molecular motors, enhanced autophagic flux, slowed cargo mutant neurons. Treatment neurons small molecule enhancer drug increases flux degradation, reduces phospho-Tau levels, accumulation without restoring defects motility. This study reveals novel effects provides window through therapeutic treatments targeting promote homeostasis.

Язык: Английский

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VezA/vezatin facilitates proper assembly of the dynactin complex in vivo

Cell Reports, Год журнала: 2024, Номер 43(11), С. 114943 - 114943

Опубликована: Ноя. 1, 2024

Cytoplasmic dynein-mediated intracellular transport needs the multi-component dynactin complex for cargo binding and motor activation. However, cellular factors involved in assembly remain unexplored. Here, we found Aspergillus nidulans that vezatin homolog VezA is important assembly. affects microtubule plus-end accumulation of dynein before cargo-adapter-mediated activation, two processes both need dynactin. The contains multiple components, including p150, p50, an Arp1 (actin-related protein 1) mini-filament associated with a pointed-end sub-complex. physically interacts either directly or indirectly. Loss significantly decreases amount pulled down proteins, as well levels p50 p150 cell extract. Using various mutants, further revealed process must be highly coordinated. Together, these results shed light on vivo.

Язык: Английский

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Small molecule modulator of neuronal lysosome positioning and function resolves Alzheimers Disease-linked pathologies in cultured human neurons

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

Опубликована: Ноя. 5, 2024

Abstract Abnormal increase in axonal lysosome abundance is associated with multiple neurodegenerative diseases including Alzheimer’s disease. However, the underlying mechanisms and disease relevance are not fully understood. We have recently identified RH1115 as a small molecule modulator of autophagy-lysosomal pathway that regulates positioning neurons. This allowed us to manipulate neuronal distribution axons interrogate its contribution both optimal functioning pathology. demonstrate only rescues aberrant buildup autophagic lysosomal intermediates but also reduces secreted Aβ42 levels human iPSC-derived neurons lacking adaptor, JIP3. thus restoring efficient transport has an anti-amyloidogenic effect promising therapeutic strategy for Furthermore, we show enhances degradation, requires adaptor JIP4 rescue pathology JIP3 KO increases JIP4-interacting membrane protein, TMEM55B. Lastly, treatment led striking locomotor defects zebrafish larvae. Thus, which can be impactful determined molecular targets modulating abundance.

Язык: Английский

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