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, α-synuclein (α-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, α-Syn, TDP-43, and Amyloid precursor 
protein (APP)/Aβ. In HD brain, we observed reduced soluble protein (but not 
mRNA) levels of Htt, α-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, α-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, α-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, α-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.