ELECTROPHYSIOLOGICAL AND MORPHOLOGICAL CHARACTERIZATION OF HUMAN-DERIVED NEURONS CARRYING <EM >ACTG1 </EM>AND <EM>ACTB</EM> ACTIN MUTATIONS

Human actinopathies are rare autosomal dominant disorders caused by mutations in genes encoding actin. Mutations in the ACTG1 and ACTB, which encode the γ- and β-actin isoforms — key components of the neuronal cytoskeleton — lead to a subset of diseases known as non-muscle actinopathies. These conditions are frequently associated with neurological and developmental abnormalities, including pachygyria, epilepsy, and intellectual disability.
During neuronal development, the actin cytoskeleton plays a crucial role in neurite formation, elongation and branching, as well as in channel distribution, signal transduction, synapse formation, and neuronal migration. Mutations in actin genes can alter the stability or polymerization process of actin filaments, thereby impairing the protein's functionality and disrupting cytoskeletal dynamics.
As of now, the mechanisms linking actin dysregulation to neurological disorders remain largely unresolved.
This study aims to elucidate how mutations in actin genes affect neuronal morphology and functionality by using neurons differentiated from patient-derived induced pluripotent stem cells carrying mutations in ACTG1 and ACTB. Through electrophysiology, immunofluorescence, and complementary techniques, we assessed the impact of these mutations on neuronal activity and structural organization, providing insight into isoform-specific contributions of actin to neuronal physiology.
Our results show significant differences in the amplitude of voltage-dependent currents and in neurite arbor complexity in mutant neurons compared to controls, highlighting profound changes in both neuronal functionality and morphology.
Future studies will focus on uncovering the molecular mechanisms underlying these morpho-functional alterations, deepening our understanding of the impact of ACTG1 and ACTB mutations on neuronal physiology and supporting the development of therapeutic approaches.