Development of a new cell model of Huntington's disease to evaluate the effectiveness of potential drugs at preclinical stages

Huntington's disease (HD) is an inherited, incurable neurodegenerative disease that primarily affects neurons in the striatum. In the present study, we successfully used an optimized cell model of HD [Kraskovskaya et al., 2023] to evaluate the effectiveness of the sigma 1 receptor agonist compound 3-PPP (N-n-propyl-3-(3-hydroxyphenyl)piperidine). We showed that striatal neurons obtained by direct reprogramming of dermal fibroblasts from HD patients (HD iSN) exhibit aggregates of mutant huntingtin, but the number of cells containing aggregates is less than 5% of the total. We also showed that the level of mitochondrial membrane potential detected by TMRM in induced HD iSNs than in induced striatal neurons derived from healthy donor fibroblasts (HC iSNs). Application of a 1uM 3-PPP solution to a culture of striatal neurons from patients with HD restores the membrane potential to the values of healthy controls. We also showed that HD iMSNs have a simpler dendritic tree structure compared to HC iSNs. In particular, there is a decrease in the number of primary dendrites, their branching, the total number of processes and the total length of dendrites. Application of 1uM 3-PPP to HD iSN culture prevents the development of morphological changes. However, application of 1uM 3-PPP does not prevent cell death of HD iMSNs caused by the removal of neurotrophic factors from the culture medium. Thus, the cell model being developed reflects the characteristic pathological phenotype of HD at the cellular level and can be used to evaluate the effectiveness of potential drugs at the preclinical stage.