Fragile polyQ assemblies cause Golgipathy in Huntington's disease

Abstract

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. Here, using high resolution imaging of cells derived from HD families, we redefine polyQ assemblies, traditionally regarded as pathogenic aggregates, as dynamic and structurally organized intracellular compartments resembling knitted-fabric patches. These assemblies closely associate with and encircle the Golgi apparatus, integrating Golgi ribbons and stacks to form a previously unrecognized polyQ assembly-Golgi complex. Mechanistically, fragmentation of polyQ assemblies is dynamically coupled with mitotic Golgi fragmentation, whereas inhibition of ADP-ribosylation factor (ARF) function by Brefeldin A disrupts and fragments the complex, revealing an intimate structural and functional coupling between polyQ assemblies and Golgi architecture. The presence of mutant HTT (mHTT) destabilizes these assemblies and complexes, altering their response to nutrient deprivation and autophagy enhancers but not to antisense oligonucleotide (ASO) therapy. Functionally, polyQ assemblies in HD cells compromise the scaffolding capacity of the Golgi apparatus, clathrin-coated vesicles, and ARF1, impair Golgi glycosylation, and promote aberrant neuronal firing activity. Collectively, these findings establish polyQ assemblies as dynamic structural regulators of Golgi organization and function and demonstrate that mHTT disrupts the homeostatic dynamics of the polyQ assembly-Golgi complex, leading to Golgipathy.