The development and maintenance of the nervous system depend on a tightly regulated intracellular transport network in which kinesin superfamily (KIF) motor proteins drive microtubule-based delivery of synaptic vesicle precursors, organelles, mRNAs, and signaling components along axons and dendrites. Disruption of this machinery underlies a clinically heterogeneous spectrum of neurodevelopmental disorders (NDDs), including intellectual disability, epilepsy, autism spectrum disorder, microcephaly, malformations of cortical development, spasticity, and axonal neuropathy. Here, we synthesize current knowledge on how kinesin dysfunction shapes neurodevelopment. We outline the physiological roles of kinesins in neuronal polarity, organelle and mitochondrial positioning, synaptogenesis, and progenitor division, and survey principal disease-associated genes, including KIF1A, KIF5A, KIF7, KIF11, KIF2A, KIF5C, and emerging members such as KIF14, KIF15, and KIF16B. We detail how distinct pathogenic mechanisms, such as loss of motility, impaired cargo coupling, motor hyperactivity, mitotic spindle defects, and disrupted ciliary signaling, converge on shared cellular endpoints, and how tubulin isotypes and posttranslational modifications further modulate motor output. In this review, we discuss translational implications, including variant-resolved diagnosis and precision strategies to restore transport, dampen pathological hyperactivity, or stabilize the microtubule track. Collectively, these advances reframe kinesinopathies as mechanistically stratified disorders of neuronal transport.
Mohammad Sadegh Shams Nosrati, Morteza Doustmohammadi, Alireza Dostmohammadi et al.· Current Issues in Molecular...· 0 citations
Primary cilia are the microtubule-based sensory organelles. The unique lipid makeup of the ciliary membrane strictly controls their signaling ability, to orchestrate tissue formation and homeostasis. Emerging evidence has demonstrated that lipids play important roles in cilia formation and cilia-related signaling, solidifying the previously proposed concept of “lipid ciliology.” The ciliary membrane exhibits a highly specialized lipid composition, including enrichment in cholesterol, sphingolipids, and specific phosphoinositides, compared with the surrounding plasma membrane. Recent studies have revealed that cholesterol and phosphoinositides function together to regulate ciliary homeostasis, protein trafficking, and signal transduction. A growing spectrum of ciliopathies, including polycystic kidney disease, retinal degeneration, cerebellar hypoplasia, and metabolic disorders, can be caused by dysregulation of lipid metabolism and lipid-modifying enzymes through impaired cilia-related signaling. Moreover, defects in cholesterol biosynthesis or intracellular lipid transport contribute to various ciliopathies, such as Smith–Lemli–Opitz syndrome and Zellweger spectrum disorders. In this review, we summarize recent advances in lipid ciliology, focusing on the underlying molecular mechanisms of ciliary cholesterol-dependent signaling in ciliopathies for emerging therapeutic strategies.
Alamgir Hasan, T. Morita, Moe Hirosawa et al.· Frontiers in Cell and Develo...· 0 citations
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