IGHMBP2 related pathological pathways in Spinal Muscular Atrophy with Respiratory Distress type 1 (SMARD1) in vitro models

Spinal Muscular Atrophy with Respiratory Distress type 1 (SMARD1) is an infant neurodegenerative disease manifesting within the first month of life with progressive distal muscular weakness and irreversible diaphragmatic palsy. Since no therapy is available, the deepening of its pathogenic mechanisms is crucial to assess new therapeutic targets and strategies. SMARD1 is caused by mutations in the IGHMBP2 gene that determine deficiency of the encoded protein Immunoglobulin µ-binding protein 2 (IGHMBP2), eventually leading to motor neurons (MNs) degeneration and disease onset. IGHMBP2 appears to have many different functions, but the actual mechanism through which its mutations cause the disease remains elusive. Hence, we explored the effects derived from IGHMBP2 reduction in in vitro models, that are induced-Pluripotent Stem Cells (iPSCs), iPSC-derived MNs and IGHMBP2-silenced SH-SY5Y. We observed an increase of apoptosis, and enhancement of DNA damage response pathway, presumably related to R-loops aberrant persistence, indicating a possible connection between IGHMBP2 deficiency and genome instability that finally lead to cell demise. In addition, gene therapy with IGHMBP2 delivery determined a decrease of apoptotic rate and DNA damage response-related protein levels, as well as less R-loops accumulation, further suggesting a link between IGHMBP2 and genome instability. Our findings lead to speculate the involvement of IGHMBP2 in aberrant R-loops resolution, a novelty that may contribute to address research towards new therapeutic targets for SMARD1.