Thanks to the research of scientists from the Laboratory of Neurodegeneration of the International Institute of Molecular and Cell Biology in Warsaw, are we close to understanding the mechanism of pathology occurring in neurons and leading to Huntington's disease? There are many indications that this may be true. Recent studies demonstrated that the SIP protein, due to its properties, may be considered as a potential target for therapy in the early stages of the pathology of this disease.

The scientists from the Laboratory of Neurodegeneration at IIMCB led by Jacek Kuźnicki, Ph.D., and their co-workers from the Centre of New Technologies at the Warsaw University have recently published in Cell and Bioscience a paper entitled “Siah-1-interacting protein regulates mutated huntingtin protein aggregation in Huntington’s disease models”.

Huntington’s disease (HD) is a neurodegenerative disorder in which mutated huntingtin protein (mHTT) aggregates. Siah1-interacting protein (SIP) acts as an adaptor protein in the ubiquitination complex and mediates protein degradation. We found that mHTT aggregation depends on SIP activity in the ubiquitination pathway in HD.

Our previous findings demonstrated that mRNA encoding SIP is elevated in the striatum in YAC128 mice, a model of HD (Czeredys et al. 2013 Front Mol Neurosci.). In the current paper, we have shown SIP dimers are elevated in this structure. We found that wildtype SIP supports the ubiquitination of mHTT, downregulates its protein levels, and consequently inhibits mHTT aggregation. However, SIP mutants that were predicted in silico to form stable dimers in vitro exhibited only residual activity toward mHTT ubiquitination and lesser protection of mHTT against aggregation. This suggests that SIP dimerization plays an important role in the progression of HD pathology.

Dysregulation of the formation of SIP dimers might occur during the presymptomatic stage of HD pathology, therefore preservation of the beneficial effects of SIP activity to slow mHTT aggregation could be considered a potential anti-HD treatment at the early stage of HD pathology.

Full article: Ewelina Latoszek, Małgorzata Wiweger, Jan Ludwiczak, Stanisław Dunin-Horkawicz, Jacek Kuznicki*, Magdalena Czeredys* Siah-1-interacting protein regulates mutated huntingtin protein aggregation in Huntington's disease models. Cell Biosci. 2022 Mar 19;12(1):34. doi: 10.1186/s13578-022-00755-0.