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.

Effects of Human LAV-BPIFB4 Gene Therapy on the Epigenetic Clock and Health of Aged Mice

“…Discovered as a peculiarity of centenarians and long-living people, the LAV-BPIFB4 protein turned out to be a very promising therapeutic strategy to fight the aging processes. The “rejuvenating” properties of the LAV-BPIFB4 were demonstrated in pre-clinical models, with a broad spectrum of protective effects towards different pathological conditions, including inflammatory status [ 23 ], cardiovascular problems [ 21 ] and Huntington’s disease [ 27 ]. Interestingly, recent evidence demonstrated that LAV delivery caused a rejuvenation of the hearts of old mice by a human equivalent of more than ten years [ 22 ].…”

“…However, since the causality relationship between inflammation and epigenetic changes in aging is still to be elucidated (whether the pro-inflammatory environment induces epigenetic aging, or age-related epigenetic modifications dysregulate inflammatory pathways), we can only speculate if the LAV effect on epigenetic aging is a direct action or a consequence of the reduced inflammation. Nevertheless, a direct impact of the LAV therapy on epigenetic modifications is not to be excluded, given that LAV-BPIFB4 showed a nuclear localization [ 35 ] and an effect on histone-mediated chromatin remodeling has been previously demonstrated [ 27 ].…”

“…Collectively, previous data suggest that (i) the liver was transduced by the viral vector and (ii) the upregulation in vessels or immune cells of LAV-BPIFB4-treated mice was likely due to an uptake of circulating protein and not to an induction of the endogenous murine gene. At the molecular level, the stable expression of the LAV-BPIFB4 isoform in cultured neurons was shown to reduce DNA damage and to impact epigenetic histone modification and consequent chromatin condensation through the reduction of methylated histone 3 levels [ 27 ].…”

m6A RNA modification of mHttintron 1 regulates the generation ofHtt1ain Huntington’s Disease

“…To evaluate how m6A levels in Htt intron 1 impacts HD pathology we performed site-specific manipulation of m6A levels and DNA damage was evaluated in ST Hdh Q111/Q111 cells which are known to show an augmentation of stress pathways, activated DNA damage response and apoptotic signals 27,78 . Our results indicate that targeted demethylation of intron 1 reduces DNA damage as observed by fewer positive nuclei for γH2AX and formation of a smaller number of foci per nuclei.…”

Neurodegenerative Diseases: Molecular Mechanisms and Therapies

“…In this context, there is a substantial clinical need yet unmet, as there are currently no clinically validated treatment medicines or therapies that can slow or stop neurodegeneration and disease progression in HD. In this Special Issue, Cattaneo et al demonstrate that LAV-BPIFB4 generates neuroprotection in the striatum-derived STHdh cell line, an in vitro model of HD [ 10 ].…”