Fragile polyQ assemblies cause Golgipathy in Huntington’s disease

Abstract Huntingtin (HTT) is a naturally aggregating protein that causes Huntington’s disease (HD) when its polyglutamine (polyQ) tract exceeds 38 repeats. Despite its importance, the biology of HTT aggregates remains poorly defined. Utilizing high-resolution imaging of HD family-derived cells, we have redefined polyQ assemblies—formerly viewed as pathogenic aggregates—as dynamic structures resembling knitted-fabric patches. These assemblies encircle the Golgi apparatus, integrating ribbons and stacks to form a functional polyQ assembly-Golgi complex and attaching clathrin vesicles. Mechanistically, we show that the fragmentation of polyQ assemblies is dynamically coupled with mitotic Golgi fragmentation and that treatment with the ARF inhibitor Brefeldin A splits and fragments the complex. The presence of mutant HTT (mHTT) ’crisps’ these assemblies and complexes, altering their response to nutrient deprivation and autophagy enhancers but not to antisense oligonucleotide (ASO) therapy. The polyQ assembly in HD cells also reduces the scaffolding capacity of the Golgi apparatus, clathrin vesicles, and ARF1, impairing Golgi functions. Our results demonstrate that mHTT disrupts the homeostatic dynamics of the polyQ assembly-Golgi complex, inducing a ’Golgipathy’ by crippling Golgi structure and function.