HTT

Cilia effects upon perturbation of HTT

Loss-of-function effect:

Decreased cilia number

Overexpression effect:

Longer cilia

Ciliogenesis screen results (2 screens)

• Wheway et al. 2015 (siRNA) [siRNA]: Ciliogenesis Defect (z=-2.96) PMID:26167766
• Breslow et al. 2018 (CRISPR) [CRISPR]: No Significant Effect PMID:29459680

Phenotypes

Mouse phenotype:

embryonic lethality prior to organogenesis, increased grip strength, preweaning lethality, complete penetrance

Subcellular localization

cilia, cytosol, endosome, microtubules, nucleus

Functional category

• Ciliary assembly/disassembly
• Trafficking (BBSome, small GTPases, vesicular transport, ATPases)
• Actin & cytoskeleton regulation
• Protein processing & maturation
• Signaling (Hedgehog, GPCRs, ion channels)
• Transcription regulation

Function

Mutated in Huntington's Disease. Scaffolding protein required for vesicular transport via interactions with and motor protein cargo adaptors such as HAP1 and dy ctin. Functio l role in autophagy (26160070). Essential for protein trafficking to the centrosome and normal ciliogenesis. Retrograde trafficking of PCM1 regulated by HTT and HAP1 to control ciliogenesis (21985783). Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway … In the absence of Htt or HAP1 expression, mislocalization of PCM1 reduced primary cilium formation in neurons and glia in culture. (21985783) Mutant Htt drives increased ciliogenesis and the formation of hypermorphic primary cilia, whereas loss of Htt results in reduced ciliogenesis.(21985782) Some GPCRs … HTT localizes in diverse types of cilia — including … non-motile sensory cilia of neurons. (25989602) Primary cilia structure is defective in HD … polyQ-HTT also accumulates in primary cilia. (26160070)

Model organism evidence