| Summary: | Huntington's disease is an autosomal dominant inherited neurodegenerative disease, with cognitive, motor and psychiatric defects and no known therapy. Altered lipid metabolism and lysosomal dysfunction have been seen in Huntington's disease (HD), including lysosomal expansion, a key feature of a type of disease known as lysosomal storage disorders (LSDs). HD shares similarities with one LSD in particular, Niemann- Pick type C (NPC), suggesting common mechanisms. We have identified NPC-like phenotypes in HD models, including lipid storage, trafficking defects, and lysosomal Ca2+ dysfunction, and the NPC protein NPC1 directly interacts with both normal and mutant huntingtin. We therefore tested the approved NPC therapy miglustat in HD models, and found beneficial effects. Lipid trafficking, Ca2+ signalling and lysosomal storage phenotypes in HD iPSC-derived neuronal cells were improved after miglustat treatment, and climbing ability in Drosophila melanogaster HD models was partially improved. Nucleic acid vectors are an essential tool in HD research and therapy. Lipid- and polymer-based vectors enter the cell via the endocytic system, and may cause altered function. Use of these vectors alone induced lysosomal expansion, phospholipid storage, and altered expression of endocytic proteins, potentially producing artefacts or interfering with delivery of therapies. We have found evidence that HD has lysosomal storage defects which may be due to disruption of NPC1, a previously unidentified component of HD pathology. Our observations also support the theory that huntingtin may be associated with the lysosome under normal as well as pathogenic conditions. The presence of related mechanisms in these two diseases suggests that knowledge from NPC and the LSD field may be useful in HD, and we have demonstrated that the NPC1 therapy miglustat is beneficial in HD models, a finding which will be developed to therapeutic tests in HD patients.
|
|---|
