I022 Defective polysialic acid (polysia) metabolism is a druggable target in Huntington’s disease

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Background Evidence indicates that defective metabolism of sialic acid-containing glycosphingolipids (gangliosides) may play a pivotal role in the pathogenesis of Huntington’s disease (HD). Besides forming gangliosides, sialic acid (Sia) occurs naturally at the end of sugar chains attached to the cell surface and soluble proteins. In particular, polysialic acid (polySia), a Sia polymer, represents a post-translational modification of the neural cell adhesion molecule (NCAM), which is particularly important for brain development, myelin integrity as well as synaptic stability and function. Aim The aim of this study was to investigate whether the metabolism of polySia is also impaired in HD and to explore the possibility to restore normal levels of sialylation, by using a highly cell permeant sialic acid derivative (P-NANA) in HD mice. Methods P-NANA was daily administered for 6 weeks in R6/2 mice and wild-type littermates, and for 8 weeks in zQ175 heterozygous and wild-type littermates, at dose of 2.5 mg/kg of body weight. Motor and cognitive deficits were assessed by Rotarod, Horizontal Ladder Task and Novel Object Recognition test. Results Our findings demonstrated, for the first time, that metabolism of PolySia is perturbed in different HD settings. Importantly, modulation of endogenous PolySia levels is therapeutic effective in two mouse models of the disease. Conclusions We believe that our work may contribute to clarify some still unexplored aspects of HD pathogenesis and to implement or to eventually define novel strategies for a better management of the disease.

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