ALTERED AUTOPHAGY RESPONSE IN HUNTINGTON ‘S DISEASE (HD) HUMAN NEURAL STEM CELLS IS CONTEXT-DEPENDENT

JUAN CRUZ CASABONA; FARIAS, MARIA I.; GOROJOD,R; PORTE ALCON; KISELEV, S; KOTLER,M; GATTO,E; FERNANDO JUAN PITOSSI

São Paulo

Simposio; São Paulo International Symposium, from Concept to Clinic: Advances in Stem Cell Researc; 2023

ISSCR

Huntington´s Disease (HD) is an autosomal dominant and progressive neurodegenerative disease characterized by involuntary movements, cognitive impairment, andneuropsychiatric symptoms. The mechanisms underlying HD pathogenesis are complex. Both loss and gain of function of mutant Huntingtin contribute to cause a wide array of neuronal dysfunctionsaffecting cell signaling, gene transcription, vesicle trafficking, axonal transport, cellular lysosomal autophagy, cell and mitochondrial metabolism as well as neurotransmission.Although, sphingosine 1-phosphate (S1P) signaling has been involved in several pathways related to neurodegenerative diseases, data regarding a neuroprotective role of the S1P receptors (S1Pr)stimulation still remains controversial (Newton J. et al, FASEB J. 2017 Apr;31(4):1719-1730, Lucaciu A. et al, Cells. 2020 Jun 22;9(6):1515.). Fingolimod (FYT720) is a sphingosine analog currently used for treatment of multiple sclerosis (MS), which proved to improve motor function, survival and reduce brain atrophy in HD animal models, drastically slowing the progression of the disease. But, despite its efficacy, this molecule has the risk of lymphopenia and bradycardia in patients. Since FYT720 demonstrated its clinical efficacy in MS efforts has been made to find more selective S1Pr agonists.The S1P axis is involved in many cellular processes such as apoptosis, autophagy, and mitochondrial function which are also involved in several neurological diseases (Lucaciu A. et al, 2020). Therefore this pathway is a promising target to new neurological therapies. Recently, Siponimod (BAF312), a molecule that modulates S1Pr1 and 5, has been synthesized, which may exert most of FTY720 benefits without lymphopenia and bradycardia, but its effects on HD or the underling processes that are involved in this disease in relation to this molecule has not been studied.Finally, Neural stem cells (NSC) derived from human induced pluripotent stem cells (hiPSc) from HD patients retain several characteristics of this disease and therefore, it has been proposed to usethese NSCs to test new candidate drugs for future therapies against HD.