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

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Abstract

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.

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Acknowledgements

This work was supported by the Canadian Institute of Health Research (CIHR, Grant # 272311) to S.S.H., and Fonds de Recherche du Québec en Santé (FRQS) provided salary support to S.S.H. I.S-A. was supported by a CIHR-Huntington Society of Canada postdoctoral fellowship and A.T. received a FRQS scholarship. Special thanks to Sergio Ewane Ebouele of the Statistical Consulting Service at the Université Laval for his advice. We are thankful to Dr. Peter Davies (Feinstein Institute for Medical Research, NY, USA) for the generous gift of anti-tau antibodies. The Harvard Brain Tissue Resource Center provided tissues and is supported in part by HHSN-271-2013-00030C. The authors are very grateful to all study participants and their families who have contributed to the NIH Neurobiobank.

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  1. Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval, CHUL, 2705 Boul. Laurier, P0-9800, Québec, QC, G1V 4G2, Canada

    Isabelle St-Amour, Andréanne Turgeon, Claudia Goupil, Emmanuel Planel & Sébastien S. Hébert

  2. Département de psychiatrie et de neurosciences, Université Laval, Québec, QC, G1V 0A6, Canada

    Isabelle St-Amour, Andréanne Turgeon, Claudia Goupil, Emmanuel Planel & Sébastien S. Hébert

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St-Amour, I., Turgeon, A., Goupil, C. et al. Co-occurrence of mixed proteinopathies in late-stage Huntington’s disease. Acta Neuropathol 135, 249–265 (2018). https://doi.org/10.1007/s00401-017-1786-7

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