Dynactin knockdown leads to synuclein aggregation by blocking autophagy in a zebrafish model of Parkinson's disease

Brazilian Journal of Medical and Biological Research, Journal Year: 2025, Volume and Issue: 58

Published: Jan. 1, 2025

Axons of dopaminergic neurons projecting from substantia nigra to striatum are severely affected in the early stage Parkinson's disease (PD), with axonal degeneration preceding loss cell bodies. Our previous study indicated that dysfunctional retrograde transport could lead death resulting PD (10.1111/j.1471-4159.2008.05526.x). However, dynein, as main molecule involved transport, was not affected. This aimed verify hypothesis dynactin rather than dynein may be one key factors PD. Dynactin morpholino used inhibit expression transgenic (Vmat2:GFP) zebrafish, a significant decrease diencephalon dopamine and synuclein aggregation basal plate region. In SH-SY5Y line, dynactin-siRNA knockdown resulted shifting dispersed distribution concentration synapses cytoplasm near axons, fusion rate decreased, especially which blocked α-synuclein autophagy flow. results linked gene dysfunction microtubule system, suggesting contributing

Language: Английский

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Physiological roles of chloride ions in bodily and cellular functions

The Journal of Physiological Sciences, Journal Year: 2023, Volume and Issue: 73(1)

Published: Nov. 15, 2023

Physiological roles of Cl-, a major anion in the body, are not well known compared with those cations. This review article introduces: (1) Cl- bodily and cellular functions; (2) range cytosolic concentration ([Cl-]c); (3) whether [Cl-]c could change cell volume under an isosmotic condition; (4) conditions where multiple transporters channels contribute to influx efflux state; (5) be large enough act as signals; (6) effects on cytoskeletal tubulin polymerization through inhibition GTPase activity polymerization-dependent biological activity; (7) proliferation; (8) Cl--regulatory mechanisms ciliary motility; (9) sweet/umami taste receptors; (10) with-no-lysine kinase (WNK); (11) regulation epithelial Na+ transport; (12) relationship between H+ body functions.

Language: Английский

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Myelination by signaling through Arf guanine nucleotide exchange factor

Journal of Neurochemistry, Journal Year: 2024, Volume and Issue: unknown

Published: June 18, 2024

Abstract During myelination, large quantities of proteins are synthesized and transported from the endoplasmic reticulum (ER)‐trans‐Golgi network (TGN) to their appropriate locations within intracellular region and/or plasma membrane. It is widely believed that oligodendrocytes uptake neuronal signals neurons regulate endocytosis‐ exocytosis‐mediated trafficking major myelin such as myelin‐associated glycoprotein (MAG) proteolipid protein 1 (PLP1). The small GTPases adenosine diphosphate (ADP) ribosylation factor (Arf) family constitute a group signal transduction molecules act regulators for signaling, vesicle sorting, or membrane in cells. Studies on mice deficient Schwann cell–specific Arfs‐related genes have revealed abnormal myelination formation peripheral nerves, indicating Arfs‐mediated signaling required However, complex roles these events remain poorly understood. This review aims provide an update transduction, focusing Arf its activator ArfGEF (guanine nucleotide exchange Arf) Future studies expected important information regarding cellular physiological processes underlying cells function modulating neural activity. image

Language: Английский

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Aging Differentially Affects Axonal Autophagosome Formation and Maturation

Autophagy, Journal Year: 2023, Volume and Issue: 19(12), P. 3079 - 3095

Published: July 18, 2023

Misregulation of neuronal macroautophagy/autophagy has been implicated in age-related neurodegenerative diseases. We compared autophagosome formation and maturation primary murine neurons during development through aging to elucidate how affects autophagy. observed an decrease the rate leading a significant density autophagosomes along axon. Next, we identified surprising increase autophagic vesicles from aged mice. While did not detect notable changes endolysosomal content distal axon early aging, observe loss acidified late aging. Interestingly, found that were transported more efficiently adult mice than young This efficient transport both proximal is maintained but lost Our data indicate does negatively impact vesicle nor later stages However, alterations efficiency reveal differentially impacts distinct aspects

Language: Английский

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Driving autophagy – the role of molecular motors

Journal of Cell Science, Journal Year: 2024, Volume and Issue: 137(3)

Published: Feb. 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.

Language: Английский

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Unraveling the interplay of kinesin-1, tau, and microtubules in neurodegeneration associated with Alzheimer’s disease

Frontiers in Cellular Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: Oct. 23, 2024

Alzheimer’s disease (AD) is marked by the gradual and age-related deterioration of nerve cells in central nervous system. The histopathological features observed brain affected AD are aberrant buildup extracellular intracellular amyloid-β formation neurofibrillary tangles consisting hyperphosphorylated tau protein. Axonal transport a fundamental process for cargo movement along axons relies on molecular motors like kinesins dyneins. Kinesin’s responsibility transporting crucial within neurons implicates its dysfunction impaired axonal AD. Impaired motor proteins, with dysregulated signaling pathways, contribute significantly to synaptic impairment cognitive decline Dysregulation tau, microtubule-associated protein, emerges as player, destabilizing microtubules disrupting kinesin-1. Kinesin-1 superfamily members, including kinesin family members 5A, 5B, 5C, light chain, intricately linked pathology. However, inconsistencies abundance patients underline necessity further exploration into mechanistic impact these proteins neurodegeneration disruptions across spectrum neurological conditions. This review underscores significance kinesin-1’s anterograde It emphasizes need investigations underlying mechanisms protein various Despite current limitations scientific literature, our study advocates targeting autophagy dysfunctions promising avenues novel therapeutic interventions diagnostics

Language: 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), Journal Year: 2024, Volume and Issue: unknown

Published: April 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.

Language: Английский

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The expanding clinical and genetic spectrum of DYNC1H1-related disorders

Brain, Journal Year: 2024, Volume and Issue: 148(2), P. 597 - 612

Published: June 7, 2024

Abstract Intracellular trafficking involves an intricate machinery of motor complexes, including the dynein complex, to shuttle cargo for autophagolysosomal degradation. Deficiency in axonemal chains, as well cytoplasmic light and intermediate have been linked with ciliary dyskinesia skeletal dysplasia. The 1 heavy chain protein (DYNC1H1) serves a core complex retrograde neuronal axons. Dominant pathogenic variants DYNC1H1 previously implicated peripheral neuromuscular disorders (NMD) neurodevelopmental (NDD). As heavy-chain is ubiquitously expressed, apparent selectivity dyneinopathy phenotypes remains currently unaccounted for. Here, we aimed evaluate full DYNC1H1-related clinical, molecular imaging spectrum, multisystem features novel presenting throughout life. We identified 47 cases from 43 families heterozygous (aged 0–59 years) collected phenotypic data via comprehensive standardized survey clinical follow-up appointments. Most patients presented divergent unrecognized neurological features, leading significant delays genetic testing establishing correct diagnosis. Neurological include autonomic rarely described behavioral disorders, movement periventricular lesions. Sensory neuropathy was nine (median age onset 10.6 years), which five were only diagnosed after second decade life, three had progressive age-dependent sensory neuropathy. Novel included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies manifestations, resembling spectrum other dyneinopathies. also biphasic disease course developmental regression first and, following period stability, neurodegenerative progression Of note, observed several whom neurodegeneration appeared be prompted by intercurrent systemic infections double-stranded DNA viruses (Herpesviridae) or single-stranded RNA (Ross River fever, SARS-CoV-2). Moreover, exacerbated viral regardless and/or severity disorder indicating role anti-viral immunity health. In summary, our findings expand beyond suggest life-long continuum age-related due deficient intracellular trafficking. This study will facilitate early diagnosis improve counselling health surveillance affected patients.

Language: Английский

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An initial HOPS-mediated fusion event is critical for autophagosome transport initiation from the axon terminal

Autophagy, Journal Year: 2024, Volume and Issue: 20(10), P. 2275 - 2296

Published: June 20, 2024

In neurons, macroautophagy/autophagy is a frequent and critical process. the axon, autophagy begins in axon terminal, where most nascent autophagosomes form. After formation, must initiate transport to exit terminal move toward cell body via retrograde transport. During these mature through repetitive fusion events. Complete lysosomal cargo degradation occurs largely body. The precipitating events stimulate autophagosome have been debated but their importance clear: disrupting neuronal or detrimental health function. We identified HOPS complex as essential for early maturation consequent initiation of from terminal. yeast mammalian cells, controls between late endosomes with lysosomes. Using zebrafish strains loss-of-function mutations

Language: Английский

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Neuronal autophagosomes are transported to astrocytes for degradation

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

Published: Sept. 4, 2024

Abstract Autophagy is a vital catabolic process responsible for the degradation of cytosolic components, playing key role in cellular homeostasis and survival. At synapses, autophagy crucial regulating neuronal activity utilizes specialized machinery. While considerable progress has been made understanding initiation autophagosome formation, mechanisms governing clearance autophagosomes from synaptic sites remain poorly understood. Here, we identify novel pathway which astrocytes actively participate pre-synaptic autophagosomes. Using neurons derived human induced pluripotent stem cell (hiPSC) lines expressing fluorescent markers chimeric mouse models, demonstrate that autophagosomal vesicles are physically transferred to astrocytes, enhanced when suppressed. Autophagosome transfer does not require direct physical contact, but it Dynamin cholesterol-dependent endocytosis internalized ultimately fuse with astrocytic lysosomes. Our findings reveal previously unrecognized mechanism slow axonal retrograde transport their nearby astrocytes.

Language: Английский

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