Neuropathology in Huntington’s Disease: A Balancing Act between Neurodegeneration and Aggregates

Abstract

Neuropathology of Huntington’s disease (HD) presents with progredient neuronal cell loss mainly in the striatum, but also in multiple other brain areas suggesting HD as a multisystem neurodegenerative disorder. Mutant huntingtin aggregates are the characteristic hallmark of HD. The aggregates are misfolded proteins varying in location, form, size and structural composition indicating a complex involvement in neurotoxicity. The question if and how the aggregates and many interacting protein partners may lead to cell death is continuously a matter of debate. The role of mutant huntingtin is more than ever of paramount importance as present genetic therapeutic approaches try to target downregulation of the Huntingtin gene expression and/or lowering the corresponding protein. In this context—and these aspects are focussed—it is of crucial interest to elucidate the regional distribution as well as the cellular and subcellular localization of aggregates in established animal models of HD and in affected HD brains.