Primary Cilia Dysfunction in Neurodevelopmental Disorders beyond Ciliopathies

Abstract

Primary cilia are specialized, microtubule-based structures projecting from the surface of most mammalian cells. These organelles are thought to primarily act as signaling hubs and sensors, receiving and integrating extracellular cues. Several important signaling pathways are regulated through the primary cilium including Sonic Hedgehog (Shh) and Wnt signaling. Therefore, it is no surprise that mutated genes encoding defective proteins that affect primary cilia function or structure are responsible for a group of disorders collectively termed ciliopathies. The severe neurologic abnormalities observed in several ciliopathies have prompted examination of primary cilia structure and function in other brain disorders. Recently, neuronal primary cilia defects were observed in monogenic neurodevelopmental disorders that were not traditionally considered ciliopathies. The molecular mechanisms of how these genetic mutations cause primary cilia defects and how these defects contribute to the neurologic manifestations of these disorders remain poorly understood. In this review we will discuss monogenic neurodevelopmental disorders that exhibit cilia deficits and summarize findings from studies exploring the role of primary cilia in the brain to shed light into how these deficits could contribute to neurologic abnormalities.

Extracellular vesicle-mediated delivery of anti-miR-106b inhibits morphine-induced primary ciliogenesis in the brain

“…Moreover, cilia dysfunction has been implicated in various neurological disorders, including Alzheimer’s disease, ciliopathies, and certain types of brain cancer. 43 , 75 , 76 The findings reported in this study may have implications for developing new treatments for these disorders, as targeting cilia function may be a novel therapeutic approach. Additional research is required to ascertain the degree to which the results presented in this study are applicable to these conditions.…”

Proteome-Wide Assessment of Clustering of Missense Variants in Neurodevelopmental Disorders Versus Cancer

“…These proteins are important for transfer of lipids and other members of the protein family have been implicated in neurodevelopmental and neurodegenerative disorders (72, 73). A recent preprint has also indicated a role for BLTP2 in the regulation of primary cilia (74); an area of molecular interest in neurodevelopmental disorders (75).…”

The Primary Cilium and its Hedgehog Signaling in Nociceptors Contribute to Inflammatory and Neuropathic Pain

“…Another primary cilium-dependent cellular signaling pathway that has been found to contribute to nociception is the wingless-related integration site (Wnt)/b-catenin signaling pathway [89][90][91][92][93][94][95] . Ciliary proteins are not only necessary for the regulation of certain types of Wnt signaling but also include effectors downstream of Wnt [96][97][98][99] . Of note, inhibitors of Wnt/b-catenin signaling have been reported to attenuate vincristine-and paclitaxel-induced CIPN [100][101][102] , and Wnt has been shown to be able to enhance neuronal excitability, producing peripheral sensitization 103,104 .…”