Age-related neurodegenerative diseases are becoming more prevalent as human lifespan increases. Modeling human aging is challenging in the lab. We use transdifferentiation via an all-in-one lentiviral vector to directly reprogram human donor-derived fibroblasts into induced neurons (iN). The advantage of this methodology is the maintaining of age and disease-related signatures of the donor cells as iNs bypass the intermediary cell rejuvenation.Huntington’s disease (HD) is an autosomal dominant age-related neurodegenerative disorder caused by a mutated Huntingtin (HTT) gene containing an expansion of CAG repeats. HD-iNs display a cell type specific alteration in proteins linked to autophagy through the AMPK pathway, only present in the HD-iNs but not in the parental fibroblast. In HD both AMPK and autophagy have neuroprotective roles, downregulation or hyperactivation of these pathways have worsened the disease.In this project we aim to target the AMPK pathway as a therapeutic strategy in HD-iNs. To quantitatively measure AMPK activity, we will transfect U2OS and RPE-1 cell lines with ExRai AMPKAR, an already published AMPK sensor. We will screen for AMPK affecting drugs using a library of 2401 FDA approved compounds. We will verify the effect of the positive compounds in our HD-iN model and look for disease modifying changes. Top candidates that can efficiently rescue autophagy and elaborate the reduced neuronal complexity of the HD-iNs will be functionally characterized using patch-clamp electrophysiology. Confirmed and carefully validated compounds can potentially be endorsed for drug repurposing and tested further in clinical trials.