Different mechanisms link gain and loss of kinesin functions to axonal degeneration

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Abstract Axons are the slender, often meter-long projections of neurons that form biological cables wiring our bodies. Most these delicate structures must survive for an organism’s lifetime, meaning up to a century in humans. Long-term maintenance and sustained functionality axons requires motor protein-driven transport distributing life-sustaining materials organelles places need. It seems therefore plausible loss function can cause axon degeneration; however, also gain-of-function conditions were linked disorders including neuron disease or spastic paraplegia. To understand this phenomenon, we studied ∼40 genetic manipulations proteins, cargo linkers regulators reactive oxygen species one standardised Drosophila primary system. Using axonal microtubule bundle organisation as relevant readout reflecting state integrity, found losses Dynein heavy chain, KIF1A/Unc-104 KIF5/Kinesin chain (Khc) all disintegration chaotically curled microtubules. Detailed functional studies Khc its adaptor proteins revealed mitochondrial lysosomal ROS dyshomeostasis, which is condition inducing MT-curling fly mouse alike. We find hyper-activated induces same phenotype, not through but directly enhanced mechanical forces. Studies with Unc-104 expression ALS-linked mutant human orthologue KIF5A suggest two mechanisms apply motors beyond Khc. discuss model explain surprising common outcome both examine relevance understanding motor-linked neurodegeneration.

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

Published: Nov. 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.

Language: Английский

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Axonal organelle buildup from loss of AP-4 complex function causes exacerbation of amyloid plaque pathology and gliosis in Alzheimer’s disease mouse model

eNeuro, Journal Year: 2024, Volume and Issue: 11(12), P. ENEURO.0445 - 24.2024

Published: Dec. 1, 2024

Lysosomes and related precursor organelles robustly build up in swollen axons that surround amyloid plaques disrupted axonal lysosome transport has been implicated worsening Alzheimer's pathology. Our prior studies have revealed loss of Adaptor protein-4 (AP-4) complex function, linked primarily to spastic paraplegia (HSP), leads a similar lysosomes structures we term “AP-4 dystrophies.” Surprisingly, these AP-4 dystrophies were also characterized by enrichment components APP processing machinery, β-site cleaving enzyme 1 (BACE1) Presenilin 2. examining whether the abnormal buildup resulting from could lead amyloidogenesis function an disease model resulted strong increase size abundance hippocampus corpus callosum as well increased microglial association with plaques. Interestingly, found further secretase, BACE1, swellings Alzheimer mice lacking compared those having normal suggestive amyloidogenic under this condition. Additionally, exacerbation plaque pathology was region specific it did not cortex. The burden dystrophies/AP-4 higher cortex, establishing critical role AP-4-dependent maturation regulating protein processing.

Language: Английский

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Chronic Oxidative Stress and Stress Granule Formation in UBQLN2 ALS Neurons: Insights into Neuronal Degeneration and Potential Therapeutic Targets

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(24), P. 13448 - 13448

Published: Dec. 15, 2024

The pathogenesis of neurodegenerative diseases results from the interplay between genetic and environmental factors. Aging chronic oxidative stress are critical contributors to neurodegeneration. UBQLN2, a ubiquitin-related protein, aids in protein degradation protects against stress. In ALS neurons harboring UBQLN2 mutations, accelerates pathological changes, yet precise mechanisms remain unclear. Using induced motor (iMNs) derived P497H iPSCs, we observed ALS-like phenotypes, including TDP-43 mislocalization, increased cell death, reduced viability. Sodium arsenite (SA)-induced triggered granule formation, while autophagy dysfunction exacerbated neuronal degeneration. CHX bosutinib treatments ubiquitinated accumulation alleviated degeneration, highlighting potential therapeutic pathways. These findings emphasize role formation ALS, offering insights into novel targets.

Language: Английский

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