Co-occurrence of mixed proteinopathies in late-stage Huntington's disease

Accumulating evidence highlights the potential role of mixed proteinopathies (i.e., abnormal protein aggregation) in the development of clinical manifestations of neurodegenerative diseases (NDD). Huntington's disease (HD) is an inherited NDD caused by autosomal-dominant expanded CAG trinucleotide repeat mutation in the gene coding for Huntingtin (Htt). Previous studies have suggested the coexistence of phosphorylated-Tau, alpha-synuclein (alpha-Syn) and TAR DNA-binding protein 43 (TDP-43) inclusions in HD. However, definite evidence that HD pathology in humans can be accompanied by other proteinopathies is still lacking. Using human post-mortem putamen samples from 31 controls and 56 HD individuals, we performed biochemical analyses of the expression, oligomerization and aggregation of Tau, alpha-Syn, TDP-43, and Amyloid precursor protein (APP)/A beta. In HD brain, we observed reduced soluble protein (but not mRNA) levels of Htt, alpha-Syn, and Tau. Our results also support abnormal phosphorylation of Tau in more advanced stages of disease. Aberrant splicing of Tau exons 2, 3 (exclusion) and 10 (inclusion) was also detected in HD patients, leading to higher 0N4R and lower 1N3R isoforms. Finally, following formic acid extraction, we observed increased aggregation of TDP-43, alpha-Syn, and phosphorylated-Tau during HD progression. Notably, we observed that 88% of HD patients with Vonsattel grade 4 neuropathology displayed at least one non-Htt proteinopathy compared to 29% in controls. Interestingly, alpha-Syn aggregation correlated with Htt, TDP-43 and phosphorylated-Tau in HD but not in controls. The impact of this work is twofold: (1) it provides compelling evidences that Tau, alpha-Syn and TDP-43 proteinopathies are increased in HD, and (2) it suggests the involvement of common mechanisms leading to abnormal accumulation of aggregation-prone proteins in NDD. Further studies will be needed to decipher the impact of these proteinopathies on clinical manifestation of HD.