The HEK293T cells manage overload by the overexpressed full-length Htt variants via proteasome activation

Gotmanova, N.N.; Bobik, T.V.; Kriachkov, V.A.; Ezhov, A.A.; Bacheva, A.V.

Авторы: Gotmanova Nataliia N., Bobik Tatiana V., Kriachkov Viacheslav A., Ezhov Alexander A., Bacheva Anna V.
Журнал: Biochimie
Том: 240
Год издания: 2026
Издательство: Elsevier BV
Местоположение издательства: Netherlands
Первая страница: 59
Последняя страница: 75
DOI: 10.1016/j.biochi.2025.10.014
Аннотация: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a pathological mutation that results in the abnormal expansion of more than 37 consecutive trinucleotide repeats (CAG) in the HTT gene. These repeats encode the polyglutamine tract (polyQ tract) in the huntingtin protein (Htt). Progressive lethal Huntington's chorea is characterized by impaired motor activity and marked cerebral atrophy. The disease affects neurons in specific areas of the central nervous system, mainly GABAergic neurons in the striatum and cortex. It is believed that the neuron-specific proteotoxicity of mutant Htt (mHtt) results from its conformational instability and tendency to aggregate due to elongation of the polyQ-tract. However, recent structural findings challenge these assumptions. To elucidate some key aspects of the molecular mechanisms of HD, we describe the transient expression of full-length normal or mutant huntingtin in HEK293T eukaryotic cells, and options of isolation and purification of huntingtin variants according to the optimized procedure. The short-termed overexpression of Htt/mHtt has been demonstrated to be associated with elevated proteasome and non-proteasome caspase activity and change in subunit expression. The cellular response to mHtt production manifested primarily as an increase in β1, β5i and in less extent β1i subunits as well as 11Sαβ expression, as observed through both Western blot and RT-qPCR. The microscopy study also revealed an enhancement in the β1i subunit content in HEK293T cells overexpressed Htt and especially mHtt suggesting an immunoproteasome activation.KeywordsHuntingtin Polyglutamine disease Proteasome Proteolysis
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The HEK293T cells manage overload by the overexpressed full-length Htt variants via proteasome activationстатья

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