Pharmacological stimulation of mitochondrial metabolism to promote full neuronal development in Allan-Herndon-Dudley Syndrome

Allan-Herndon-Dudley Syndrome (AHDS) is a rare X-linked disorder characterized by severe neurocognitive and motor impairments, caused by mutations in the SLC16A2 gene that encodes the MCT8 transporter, which is essential for the entry of thyroid hormone into the central nervous system. T3 deficiency in the brain profoundly disrupts neurogenesis, myelination, and synapse formation, leading to irreversible defects in nervous system development.  T3 plays a crucial role in regulating mitochondrial metabolism, an essential process that sustains the high energy demand of progenitor cells during differentiation. Recent evidence, including that generated by our group, suggests that T3 deficiency impairs mitochondrial function, leading to reduced neuronal maturation. Conversely, pharmacological stimulation of mitochondrial metabolism can promote neuronal maturation even in the absence of T3, suggesting that targeting this pathway may represent a potential therapeutic strategy. Based on these premises, our project aims to gather preclinical evidence on the efficacy of mitochondrial metabolism modulation as an innovative approach for AHDS. Using cellular and mouse models of the disease, we aim to assess the impact of molecules that enhance mitochondrial biogenesis and activity on neuronal maturation, as well as their ability to reach the central nervous system and ameliorate pathological phenotypes.