The Huntingtin Transport Complex

Biochemistry, Год журнала: 2025, Номер unknown

Опубликована: Фев. 5, 2025

A dynamic network of scaffolding molecules, adaptor proteins, and motor proteins work together to orchestrate the movement mRNA, vesicular cargoes. Defects in intracellular transport can often lead neurodegeneration. Huntingtin (HTT) is a ubiquitously expressed protein with multitude cellular roles, including regulating various organelles. HTT remarkable its ability regulate wide range cargoes, BDNF vesicles, APP early endosomes, autophagosomes, lysosomes, mitochondria. This interaction allows huntingtin control microtubule-based by kinesin dynein, as well actin-based myosin VI. By forming complexes multiple adaptors, regulates variety cargoes guides through different stages biosynthesis, signaling, degradation. Accordingly, pathogenic polyglutamine expansions seen Huntington's Disease (HD) dysregulate complexes, resulting defects

Язык: Английский

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Anti-Parkinsonian Drugs Rescue Locomotor Deficits in JIP3 Knockout Zebrafish: Implications for Treating Patients with MAPK8IP3-related Neurodevelopmental Disorders

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 6, 2025

ABSTRACT MAPK8IP3- related neurodevelopmental disorders are a spectrum of rare conditions caused by de novo mutations in the MAPK8IP3 gene that encodes JIP3 protein. These associated with symptoms manifest children and cause brain abnormalities, profound intellectual disabilities, movement disorders, developmental delays. is required for axonal transport proteins organelles between soma synaptic terminal neurons, process critical normal development function. Homozygous loss-of-function lead to impaired aggregation cargo, which result swelling stunted elongation. Despite these severe outcomes, disease mechanisms poorly understood, no current treatments available. Here we conduct thorough morphological, behavioral, motility phenotyping knockout zebrafish identify locomotor deficits morphological abnormalities. To treatment options, used insights from expert clinicians artificial intelligence tool, mediKanren, drug candidates hypothesized improve patient or compensate loss at molecular level. We then prioritized drugs FDA-approved, safe children, readily collective efforts identified amantadine levodopa as candidate therapies rescued motor phenotypes zebrafish.

Язык: Английский

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Axonal transport of CHMP2b is regulated by kinesin-binding protein and disrupted by CHMP2b^intron5

Life Science Alliance, Год журнала: 2025, Номер 8(5), С. e202402934 - e202402934

Опубликована: Фев. 28, 2025

CHMP2b is a core component of the ESCRT pathway that catalyzes formation multivesicular bodies for endolysosomal protein degradation. Although mutation/loss-of-function promotes presynaptic dysfunction and degeneration, indicating its critical role in homeostasis, mechanisms responsible localization recruitment to synapses remain unclear. Here, we characterize axonal trafficking show transport boutons, as well cotransport with other proteins, are regulated by neuronal activity. In contrast, frontotemporal dementia–causative intron5 mutation exhibits little processive movement or presence absence Instead, vesicles exhibit oscillatory behavior reminiscent tug-of-war between kinesin dynein motor proteins. We this phenotype caused deficient binding kinesin-binding protein, which identify key regulator transport. These findings shed light on synaptic localization, their disruption .

Язык: Английский

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TBCK-deficiency leads to compartment-specific mRNA and lysosomal trafficking defects in patient-derived neurons

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 7, 2025

ABSTRACT Monogenic pediatric neurodegenerative disorders can reveal fundamental cellular mechanisms that underlie selective neuronal vulnerability. TBCK-Encephaloneuronopathy (TBCKE) is a rare autosomal recessive disorder caused by stop-gain variants in the TBCK gene. Clinically, patients show evidence of profound neurodevelopmental delays, but also symptoms progressive encephalopathy and motor neuron disease. Yet, physiological role protein remains unclear. We report human TBCKE model, derived from iPSCs homozygous for Boricua variant (p.R126X). Using unbiased proteomic analyses neurons, we find interacts with PPP1R21, C12orf4, Cryzl1, consistent being part FERRY mRNA transport complex. Loss leads to depletion C12ORF4 levels across multiple cell types, suggesting may play regulating at least some members preferentially, not exclusively, localizes surface endolysosomal vesicles colocalize lysosomes. Furthermore, TBCK-deficient neurons have reduced content axonal compartment relative soma. lysosomal dynein/dynactin adapter JIP4, which functionally exhibiting striking retrograde trafficking defects. Hence, our work reveals mediate mRNA, particularly along lysosomes compartments. TBCK-deficiency compartment-specific defects likely contribute preferential susceptibility neurodegeneration.

Язык: Английский

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

Brazilian Journal of Medical and Biological Research, Год журнала: 2025, Номер 58

Опубликована: Янв. 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

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

Frontiers in Cellular Neuroscience, Год журнала: 2024, Номер 18

Опубликована: Окт. 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

Язык: Английский

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

Autophagy, Год журнала: 2024, Номер 20(10), С. 2275 - 2296

Опубликована: Июнь 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

Язык: Английский

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Neuronal autophagosomes are transported to astrocytes for degradation

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

Опубликована: Сен. 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.

Язык: Английский

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