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Abstract <p>Primary cilia are solitary, antenna-like organelles that project from the surface of most vertebrate cells. They consist of a microtubule-based axoneme extending from a modified centriole (basal body) and enclosed by a lipid bilayer membrane. For several decades after their discovery, the functions of primary cilia had remained speculative; they were even considered vestigial structures. Currently, primary cilium is recognized as essential sensory and signaling structure involved in both chemo- and mechanosensation. Its anchoring at the centrosome surrounded by a radially organized network of microtubules and ability to detect extracellular signals through the axoneme protruding beyond the cell surface and enveloped by a receptor-rich membrane, make primary cilium a unique signaling hub of the cell. The functional activity of primary cilia is critical for numerous biological processes, including embryonic development and cellular differentiation, whereas defects in ciliogenesis result in severe somatic disorders. Prominent neurological abnormalities observed in several ciliopathies have prompted investigations into the structure and function of primary cilia in other brain disorders. It has become evident that defects of neuronal primary cilia are characteristic of several monogenic neurological diseases that have not traditionally been classified as ciliopathies. A growing body of evidence indicates that many severe neurodegenerative disorders, particularly polyglutamine diseases such as Huntington’s disease, are associated with specific alterations and dysfunction of primary cilia. In this review, we summarize current knowledge on the detrimental effects of disease-causing mutant proteins on the function of primary cilium, with particular emphasis on the disruption of PCM1 (pericentriolar material&#xa0;1) trafficking by mutant huntingtin, leading to ciliary elongation and alterations in signaling pathways. We further discuss the consequences of mutant protein-induced dysfunction of this cellular antenna and analyze associated signaling pathways that may represent promising therapeutic targets. Finally, we describe potential approaches for investigating dysfunction of the neuronal signaling hub with primary cilium as an antenna.</p>

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Dysfunction of Primary Cilium in Huntington’s Disease: How Mutant Huntingtin Disrupts This Cellular Signaling Hub

  • 期刊论文

  • 发表日期：

    2026年7月31日

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  • Aleksandra S. Churkina,
  • Anton S. Shakhov,
  • Irina B. Alieva

摘要

Abstract

Primary cilia are solitary, antenna-like organelles that project from the surface of most vertebrate cells. They consist of a microtubule-based axoneme extending from a modified centriole (basal body) and enclosed by a lipid bilayer membrane. For several decades after their discovery, the functions of primary cilia had remained speculative; they were even considered vestigial structures. Currently, primary cilium is recognized as essential sensory and signaling structure involved in both chemo- and mechanosensation. Its anchoring at the centrosome surrounded by a radially organized network of microtubules and ability to detect extracellular signals through the axoneme protruding beyond the cell surface and enveloped by a receptor-rich membrane, make primary cilium a unique signaling hub of the cell. The functional activity of primary cilia is critical for numerous biological processes, including embryonic development and cellular differentiation, whereas defects in ciliogenesis result in severe somatic disorders. Prominent neurological abnormalities observed in several ciliopathies have prompted investigations into the structure and function of primary cilia in other brain disorders. It has become evident that defects of neuronal primary cilia are characteristic of several monogenic neurological diseases that have not traditionally been classified as ciliopathies. A growing body of evidence indicates that many severe neurodegenerative disorders, particularly polyglutamine diseases such as Huntington’s disease, are associated with specific alterations and dysfunction of primary cilia. In this review, we summarize current knowledge on the detrimental effects of disease-causing mutant proteins on the function of primary cilium, with particular emphasis on the disruption of PCM1 (pericentriolar material 1) trafficking by mutant huntingtin, leading to ciliary elongation and alterations in signaling pathways. We further discuss the consequences of mutant protein-induced dysfunction of this cellular antenna and analyze associated signaling pathways that may represent promising therapeutic targets. Finally, we describe potential approaches for investigating dysfunction of the neuronal signaling hub with primary cilium as an antenna.