Primary cilia and autophagic dysfunction in Huntington’s disease

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.

Autophagy and primary cilia: dual interplay

“…Although still lacking direct experimental support, a possible connection between defective PC structures in Huntington’s Disease (HD) and the described autophagy dysfunction in this disease has been recently proposed [41]. The widely recognized autophagy malfunction in HD originates at different levels, including abnormal autophagy induction, failure to selectively recognize the autophagic cargo as well as altered trafficking of the autophagic vesicles [42, 43].…”

The folding equilibrium of huntingtin exon 1 monomer depends on its polyglutamine tract

“…HD patients carry a dominant mutation in the gene that encodes huntingtin (Htt) such that the polyQ tract in the first exon is expanded to contain 36 or more Q repeats (3,4). HD progression is characterized by toxicity to neurons in the neostriatum as well as a variety of other brain regions (5). Although studies implicate specific monomeric, oligomeric, and fibrillar species of mutant Htt in neuronal toxicity (6,7), the bounty of functions served by Htt and the variety of pathways possibly relevant to toxicity in HD have made the exact mechanism or mechanisms by which polyQ expansion leads to cell death difficult to pinpoint (8).…”

“…Present address: Laboratory of Chemical Physics, NIDDK, National Institutes of Health, Bethesda, MD 20892 5. To whom correspondence should be addressed.…”

Epigenetic DNA Methylation Profiling with MSRE: A Quantitative NGS Approach Using a Parkinson's Disease Test Case

“…Histone 4 (H4K20) is a target and is methylated during mitosis and represents a specific tag for epigenetic transcriptional repression (Kalakonda et al, 2008; West et al, 2010; Malik et al, 2015). Second, HTT, is Huntington Disease Protein or Huntingtin, for which there are well established neurodegenerative actions (Gusella et al, 2014; Kaliszewski et al, 2015; Kumar et al, 2015; Labadorf and Myers, 2015). Simple literature based searches are not definitive and there is a great deal of language complexity when parsing through abstracts targeting in on just a few specific words.…”