A027 Consequence(s) of an impaired one-carbon metabolism on the pathophysiology of Huntington’s disease

<h3></h3> Several studies demonstrated that Huntington’s disease (HD) patients are hyperhomocysteinemic. This could be related to an altered one carbon metabolism (OCM). Hyperhomocysteinemia induces an irreversible fixation of homocysteine on some proteins (N-homocysteinylation) leading to their loss of function. We demonstrated the N-homocysteinylation of the huntingtin and we hypothesized that it could be an aggravating risk factor in HD in terms of early and severe symptoms. This work gave rise to the HO-HD protocol (CPP 1-21-018 ID 11541) a cohort of HD patients who will be followed longitudinally in terms of neurology and biochemistry (OCM). Fibroblast cell lines are established from a skin biopsy to investigate the N-homocysteinylation of the HTT by proximity ligation assay (Duolink®). A vitamin B deficiency animal model has also been set up in Hdh Q111 KI mice to induce hyperhomocysteinemia. Behavioural tests were performed to follow the progression of the disease and LCMS-MS analysis were done on the plasma. 68% of HO-HD patients presented alterations of the OMC and 59% are hyperhomocysteinemic. Our results show an increased HTT N-homocysteinylation, first cognitive symptoms and more rapid disease progression in these patients. HdhQ111 vitamin B-deficient mice presented hyperhomocysteinemia, alteration of the transulfuration pathway and earlier cognitive and motor disabilities. Our work highlights the relevance of assessing B vitamin and homocysteine status in HD patients and being vigilant about the presentation of the first cognitive and behavioural symptoms. Development of new biomarkers targeting the N-homocystéinylated HTT protein and strategies aiming to promote de-homocysteinylation could be new perspectives in HD.