Longevity-Associated Variant of BPIFB4 Confers Neuroprotection in the STHdh Cell Model of Huntington Disease.

ABSTRACT

Huntington's disease (HD) is caused by the production of mutant Huntingtin (mHTT), characterized by long polyglutamine repeats with toxic effects. There are currently no clinically validated therapeutic agents that slow or halt HD progression, resulting in a significant clinical unmet need. The striatum-derived STHdh cell line, generated from mHTT knock-in mouse embryos (STHdhQ111/Q111), represents a useful model to study mechanisms behind pathogenesis of HD and to investigate potential new therapeutic targets. Indeed, these cells show susceptibility to nucleolar stress, activated DNA damage response and apoptotic signals, and elevated levels of H3K9me3 that all together concur in the progressive HD pathogenesis. We have previously shown that the adeno-associated viral vector-mediated delivery of the longevity-associated variant (LAV) of BPIFB4 prevents HD progression in a mouse model of HD. Here, we show that LAV-BPIFB4 stably infected in STHdhQ111/Q111 cells reduces (i) nucleolar stress and DNA damage through the improvement of DNA repair machinery, (ii) apoptosis, through the inhibition of the caspase 3 death signaling, and (iii) the levels of H3K9me3, by accelerating the histone clearance, via the ubiquitin-proteasome pathway. These findings pave the way to propose LAV-BPIFB4 as a promising target for innovative therapeutic strategies in HD.