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Updated: Apr 7, 2026
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Primary cilia and autophagic dysfunction in Huntington's disease
M Kaliszewski1, A B Knott1, E Bossy-Wetzel1
1Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, 32827 FL, USA.
Insights
Huntington's disease (HD) involves a mutated huntingtin (HTT) gene, leading to protein aggregation and impaired autophagy. Research suggests primary cilia defects may also contribute to HD pathogenesis.
Area of Science:
- Neurodegenerative diseases
- Cellular biology
- Genetics
Background:
- Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a CAG expansion in the huntingtin (HTT) gene.
- This mutation leads to the production of mutant huntingtin protein (polyQ-HTT) with a toxic polyglutamine tail.
- Protein misfolding and aggregation are hallmarks of HD, implicating cellular housekeeping processes like autophagy in disease pathology.
Purpose of the Study:
- To review recent research on the potential links between autophagy, primary cilia, and Huntington's disease.
- To explore possible pathogenic mechanisms involving these cellular components in HD.
- To identify future research directions for understanding HD pathogenesis.
Main Methods:
- Literature review of recent studies on autophagy, primary cilia, and HD.
- Analysis of existing research suggesting a relationship between these elements.
- Speculation on pathogenic mechanisms based on current findings.
Main Results:
- Abnormal autophagy, characterized by increased induction and inefficient clearance, is observed in HD.
- Primary cilia structure is defective in HD, suggesting a link to autophagic dysfunction.
- PolyQ-HTT accumulation in primary cilia may disrupt signaling pathways or facilitate disease propagation.
Conclusions:
- Autophagic dysfunction and primary cilia defects are potentially linked in Huntington's disease pathogenesis.
- Primary cilia may play additional roles in HD, including signaling disruption and propagation of toxic protein fragments.
- Further research is needed to elucidate the precise roles of autophagy and primary cilia in HD and to explore therapeutic strategies.
Abstract:
Huntington's disease (HD) is an inherited, neurodegenerative disorder caused by a single-gene mutation: a CAG expansion in the huntingtin (HTT) gene that results in production of a mutated protein, mutant HTT, with a polyglutamine tail (polyQ-HTT). Although the molecular pathways of polyQ-HTT toxicity are not fully understood, because protein misfolding and aggregation are central features of HD, it has long been suspected that cellular housekeeping processes such as autophagy might be important to disease pathology. Indeed, multiple lines of research have identified abnormal autophagy in HD, characterized generally by increased autophagic induction and inefficient clearance of substrates. To date, the origin of autophagic dysfunction in HD remains unclear and the search for actors involved continues. To that end, recent studies have suggested a bidirectional relationship between autophagy and primary cilia, signaling organelles of most mammalian cells. Interestingly, primary cilia structure is defective in HD, suggesting a potential link between autophagic dysfunction, primary cilia and HD pathogenesis. In addition, because polyQ-HTT also accumulates in primary cilia, the possibility exists that primary cilia might play additional roles in HD: perhaps by disrupting signaling pathways or acting as a reservoir for secretion and propagation of toxic, misfolded polyQ-HTT fragments. Here, we review recent research suggesting potential links between autophagy, primary cilia and HD and speculate on possible pathogenic mechanisms and future directions for the field.
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