Huntington’s disease (HD) is an inherited neurodegenerative disorder associated with motor and cognitive decline, caused by a mutation in the poly-glutamine (polyQ) region near the N-terminus of the huntingtin (htt) protein. Expansion of the polyQ region results in the disease that is characterized by oligomeric and fibrillar aggregates of mutated protein. There is increasing evidence that lipid interactions may play a role in the toxic gain of function associated with the htt polyQ expansion, as membrane-related changes, including structural abnormalities of several organelles, are observed in HD. In particular, the accumulation of htt fibrils near the endoplasmic reticulum (ER) impinges upon the membrane, resulting in ER damage, altered dynamics, and leakage of Ca²⁺. Here, the aggregation of htt at a bilayer interface assembled from ER-derived liposomes was investigated, and fibril formation directly on these membranes was enhanced. Based on these observations, simplified model systems were used to investigate htt association with and aggregation on ER membranes. As the ER-derived liposome fractions contained residual Ca²⁺, the role of divalent cations was also investigated. In the absence of lipids, divalent cations had minimal to no impact on htt structure and aggregation. However, the presence of divalent cations (Ca²⁺ or Mg²⁺) reduced htt insertion into and association with lipid interfaces, but promoted fibril formation on lipid membranes suggesting that the ability of divalent cations to promote fibril formation on membranes is mediated by induced changes to the lipid membrane physicochemical properties. With enhanced concentrations of intracellular calcium being a hallmark of HD, the ability of divalent cations to influence htt aggregation at lipid membranes may play a role in aggregation events that lead to disease associated organelle abnormalities.

Justin Legleiter

Appearances