INTERROGATING ALS SIGNATURE IN EARLY NEURAL PROGENITOR CELLS: A DIFFERENT PERSPECTIVE

Amyotrophic lateral sclerosis (ALS) is a relentlessly fatal neurodegenerative disease characterized by a selective degeneration of upper motor neurons in motor cortex and lower motor neurons in brainstem and spinal cord, leading to rapid paralysis and death. To date, while the molecular basis of the earliest pathogenesis is still unknown, few findings highlight a compromised adult neurogenesis in ALS. Nonetheless, an increasing amount of evidence shows the pivotal role of abnormalities in energy metabolism and mitochondrial dysfunction in ALS, thus suggesting a strong association between mitochondria metabolism disorder and neurodegeneration. In this study, starting from skin biopsies, we generated a collection of induce pluripotent stem cell (iPSCs) lines from a TARDBP family carrying p.G376D mutation, spanning diverse clinical stages of the disease – asymptomatic, early symptomatic, and late symptomatic – to obtain human induced Neural Stem Cells (hiNSCs) and human induced Neural Progenitor Cells (hiNPCs). The preliminary results showed that hiNSCs carrying p.G376D mutation exhibit impairments in the growth rate, mitochondrial functionality, and ATP production compared to healthy controls. This evidence suggests that possible perturbations may occur temporally earlier starting from hiNSCs, potentially increasing the vulnerability of mature cells to subsequent degeneration. By investigating the initial dysfunctions, this study aims to provide a platform to unravel critical gaps in understanding the disease progression, paving the way for innovative and targeted treatments.