Loss of BICD2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophy

Abstract

BICD2 is a key component of the dynein/dynactin motor complex. Autosomal dominant mutations in BICD2 cause Spinal Muscular Atrophy Lower Extremity Predominant 2 (SMALED2), a developmental disease of motor neurons. In this study we sought to examine the motor neuron phenotype of conditional Bicd2-/- mice. Bicd2-/- mice show a significant reduction in the number of motor axons of the L4 ventral root compared to wild type mice. Muscle-specific knockout of Bicd2, but not motor neuron-specific Bicd2 loss, results in a reduction in L4 ventral axons comparable to global Bicd2-/- mice. Rab6, a small GTPase required for the sorting of secretory vesicles from the TGN to the plasma membrane is a major binding partner of BICD2. We therefore examined the secretory pathway in SMALED2 patient fibroblasts and demonstrated impaired flow of constitutive secretory cargoes. Together, these data indicate that BICD2 loss from muscles is a major driver of non-cell autonomous pathology with important implications for future therapeutic approaches to SMALED2. SummaryMissense mutations in the cargo adaptor protein BICD2 cause SMALED2, a developmental disease of motor neurons. In this study, the authors show that BICD2 mutations cause motor neuron loss by a non-cell autonomous mechanism determining a disabling impairment of muscle function.