Glyco-sphingo biology: a novel perspective for potential new treatments in Huntington's disease

Alba Di Pardo; Vittorio Maglione

doi:10.4103/1673-5374.215253

摘要：Huntington's disease (HD)is the most common dominantly inherited neurodegenerative disorder, mainly characterized by the progressive striatal and cortical neurodegeneration and as-sociated motor, cognitive and behavioural disturbances (Zuccato et al., 2010). The disease-causing mutation is an expansion of a CAG trinucleotide repeat (> 36 repeats) encoding a polygluta-mine stretch in the N-terminal region of huntingtin (Htt) (Zuc-cato et al., 2010), a ubiquitous protein whose function is still unclear (Zuccato et al., 2010). Expansion of the polyQ stretch endows mutantHtt (mHtt) with toxic properties, and results in the development of a broad array of undesirable effects in both neuronal and non-neuronal cells (Zuccato et al., 2010). Among all cellular dysfunctions and biochemical imbalances classically associated with HD, perturbed metabolism of (glyco) sphingolipids appears to play a crucial role in the pathogenesis of the disease. Over the last years, we and other have extensively contributed to these findings (Desplats et al., 2007; Maglione et al., 2010; Di Pardo et al., 2014, 2016). We have demonstrat-ed that genes involved in the synthesis of a specific class of sphingolipids, termed gangliosides, classically defined as sialic acid-containing glycosphingolipids most abundant in the ner-vous system and essential for many biological events (Schnaar et al., 2014), were significantly down-regulated in multiple HD pre-clinical models and importantly in fibroblasts from HD pa-tients (Maglione et al., 2010; Di Pardo et al., 2014, 2016).