Distinct Clinical Phenotypes in KIF1A-Associated Neurological Disorders Result from Different Amino Acid Substitutions at the Same Residue in KIF1A

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

Published: Feb. 27, 2025

KIF1A is a neuron-specific kinesin motor responsible for intracellular transport along axons. Pathogenic mutations cause KIF1A-associated neurological disorders (KAND), spectrum of severe neurodevelopmental and neurodegenerative conditions. While individual have been studied, how different substitutions at the same residue affect function disease progression remains unclear. Here, we systematically examine molecular clinical consequences three key domain residues-R216, R254, R307-using single-molecule motility assays genotype-phenotype associations. Our findings reveal that R216 R254 produce residue-specific effects, with some partially retaining function, whereas R307 universally abolish motility, likely due to its critical role in microtubule binding. Mutant properties correlate developmental outcomes, linked most sever impairments. These results demonstrate even single-residue can lead distinct phenotypes, highlighting finely tuned mechanochemical KIF1A. By establishing relationships, this work provides fundamental insights into KAND pathogenesis informs targeted therapeutic strategies.

Language: Английский

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Molecular Motors in Blood–Brain Barrier Maintenance by Astrocytes

Brain Sciences, Journal Year: 2025, Volume and Issue: 15(3), P. 279 - 279

Published: March 6, 2025

The blood–brain barrier (BBB) comprises distinct cell types, including endothelial cells, pericytes, and astrocytes, is essential for central nervous system (CNS) homeostasis by selectively regulating molecular transport maintaining integrity. In particular, astrocytes are BBB function, as they maintain integrity through their end-feet, which form a physical biochemical interface that enhances function selectivity. Moreover, secrete growth factors like vascular factor (VEGF) transforming factor-beta (TGF-β), regulate tight junction (TJ) proteins (e.g., claudins occludins) crucial limiting paracellular permeability. Molecular motors kinesins, dynein, myosins these astrocyte functions. By facilitating vesicular trafficking protein transport, various functions, of junctional to support integrity, the proper mitochondria localization within processes efficient energy supply, polarized distribution aquaporin (AQP)-4 at end-feet water across BBB, modulation neuroinflammatory responses. myosin modulate actomyosin dynamics process outgrowth, adhesion, migration, morphology, functional roles. Thus, motor dysregulation in can compromise increasing risk neurodegeneration. This review explores complex interplay between homeostasis, represents an attractive but poorly explored area research.

Language: Английский

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Tumbleweed: an artificial motor protein that walks along a DNA track

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

Published: March 12, 2025

Abstract Nature has used proteins to evolve molecular motors that facilitate life. Although small-molecule- and DNA-based have been synthesized, the creation of an artificial motor protein remained a goal synthetic biology. Here we describe modular approach create protein, Tumbleweed (TW). TW three legs, each with ligand-gated DNA binding domain controls track. works via Brownian ratchet mechanism where steps are effected by diffusion then rectified controlling ligands. Using single-molecule fluorescence assays microfluidic device, show directionally along track when ligand concentrations altered in sequence.

Language: Английский

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Nuclear and genome dynamics underlying DNA double-strand break repair

Nature Reviews Molecular Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 17, 2025

Language: Английский

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Decoding the complex journeys of RNAs along neurons

Nucleic Acids Research, Journal Year: 2025, Volume and Issue: 53(7)

Published: April 10, 2025

Abstract Neurons are highly polarized, specialized cells that must overcome immense challenges to ensure the health and survival of organism in which they reside. They can spread over meters persist for decades yet communicate at sub-millisecond millimeter scales. Thus, neurons require extreme levels spatial-temporal control. employ molecular motors transport coding noncoding RNAs distal synapses. Intracellular trafficking enables locally regulate protein synthesis synaptic activity. The way get loaded onto transported their target locations, particularly following plasticity, is explored below.

Language: Английский

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KIF26B promotes bladder cancer progression via activating Wnt/β-catenin signaling in a TRAF2-dependent pathway

Cell Reports, Journal Year: 2025, Volume and Issue: 44(5), P. 115595 - 115595

Published: April 19, 2025

Language: Английский

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Modulation of the Cytoskeleton for Cancer Therapy

Published: Jan. 1, 2024

Language: Английский

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