Abstract
Huntington disease (HD) represents a family of neurodegenerative diseases that are caused by misfolded proteins. The misfolded proteins accumulate in the affected brain regions in an age-dependent manner to cause late-onset neurodegeneration. Transgenic mouse models expressing the HD protein, huntingtin, have been widely used to identify therapeutics that may retard disease progression. Here we report that Berberine (BBR), an organic small molecule isolated from plants, has protective effects on transgenic HD (N171-82Q) mice. We found that BBR can reduce the accumulation of mutant huntingtin in cultured cells. More importantly, when given orally, BBR could effectively alleviate motor dysfunction and prolong the survival of transgenic N171-82Q HD mice. We found that BBR could promote the degradation of mutant huntingtin by enhancing autophagic function. Since BBR is an orally-taken drug that has been safely used to treat a number of diseases, our findings suggest that BBR can be tested on different HD animal models and HD patients to further evaluate its therapeutic effects.
Highlights
Huntington’s disease (HD) is a severe neurodegenerative disease that is characterized by chorea, dystonia, motor coordination loss, and mental deterioration
HEK293 cells transfected with the control GFP-exon1 Htt containing 20Q (Htt-20Q) did not exhibit any significant GFP signal reduction with even the highest concentration of BBR (100 μM), suggesting that BBR selectively reduces the accumulation of mutant Htt (Fig 1B) and since both Htt-20Q and Htt-120Q were both under a cytomegalovirus promoter, it suggests that BBR does not impede transfection or promoter activity
HD shares many pathological features with other neurodegenerative diseases that are caused by protein misfolding
Summary
Huntington’s disease (HD) is a severe neurodegenerative disease that is characterized by chorea, dystonia, motor coordination loss, and mental deterioration. Expansion of the polyQ repeat tract (>36Q) results in HD, and increases of over 55Q lead to fast progression juvenile-onset HD [2, 3]. The reason for this threshold is most likely that expanded polyQ repeats cause N-terminal Htt fragments to misfold, leading to abnormal protein interactions and aggregation of mutant Htt [4, 5]. The role of Htt aggregates in HD remains controversial, they result from the accumulation of mutant Htt and have been used to assess the therapeutic effects of drugs on HD
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