Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease

Abstract

IntroductionHuntington disease (HD) is an autosomal-dominant neurodegenerative disorder caused by the pathogenic expansion of the polyglutamine (polyQ) N-terminal stretch in the huntingtin protein (HTT; encoded by HTT). HD is characterized by the dysfunction and death of neurons in the brain, leading to devastating cognitive, psychiatric, and motor symptoms in patients. Studies in multiple cell and animal model systems support the notion that polyQ expansion in mutant Htt leads to the gain of new toxic functions and loss of the neuroprotective functions of the WT Htt (1).Although some of its functions are linked to transcriptional activities in health and disease, Htt is primarily a cytoplasmic protein that associates with microtubules (MTs) and vesicles. Htt regulates intracellular trafficking of various organelles, including vesicles, by interacting with the dynein/dynactin pathway (2-4). Htt facilitates MT-dependent transport by interacting directly with dynein (2) and indirectly via huntingtin-associated protein 1 (HAP1), which binds to the dynactin p150 Glued subunit (3,(5)(6)(7). In pathological situations, the Htt-HAP1-dynactin complex is altered, resulting in a reduction of vesicular transport in neurons (3). These findings show that Htt integrates vesicular transport by regulating the activity of specific protein complexes containing the dynein/dynactin and kinesin 1 complexes and adaptor proteins such as HAP1.With 2 patterns of axonemal MTs (9 + 0 in primary cilia and 9 + 2 in motile cilia), cilia are involved in sensory role, motility, and flow generation. Within the last 5 years, the importance of this

Potential function for the Huntingtin protein as a scaffold for selective autophagy

“…The association of HTT with OPTN directly links it to the RAB8 protein, important for ciliogenesis (6,41,50,51). These data support a role for HTT in ciliogenesis/ ciliophagy (52).…”

“…Conditional inactivation of HTT in the mouse forebrain at postnatal or late embryonic stages causes a progressive neurodegenerative phenotype associated with neuronal degeneration, motor phenotypes, and early mortality (5). Loss of HTT in mouse cells reduces primary cilia formation, and deletion of HTT in ependymal cells leads to alteration of the cilia layer, suggesting a role for HTT in ciliogenesis (6). Mutant HTT expression and HTT knockdown have also been found to impair axonal trafficking of vesicles, mitochondria, and autophagosomes in neurons in vitro and in vivo (7)(8)(9).…”

Primary cilia and autophagic dysfunction in Huntington’s disease

“…The Saudou group demonstrated that HTT, in conjunction with HAP1, mediates the transport of PCM1 between the cytoplasm and pericentriolar material. Their data elucidate a role for HTT in ciliogenesis through the HAP1-PCM1 pathway 74 ( Figure 4a). Significantly, they found that polyQ-HTT exhibits increased interaction with HAP1, thereby causing PCM1 accumulation at the centrosome, increased ciliogenesis and primary cilia elongation 74 ( Figure 4b).…”

“…72 Interestingly, primary cilia dysfunction has recently been implicated in late-onset neurodegenerative disorders such as Alzheimer's disease and HD. 73,74 Primary cilia are covered in a specialized receptor-dense membrane and protrude into the extracellular environment like cellular antennae. 75 To facilitate their specialized signaling functions, primary cilia are compartmentalized from the rest of the cell.…”

“…Interestingly, elongated ciliary morphology is evident in HD mice and human HD brains, in which autophagic dysfunction has been reported. 74 Primary Cilia and HD Pathogenesis Primary cilia morphology is altered in HD. The association between HTT, microtubules and motor proteins is critical for trafficking within the cell.…”