Summary
Considering the confounding systemic effects of extremely low SMN, we advocate for these studies to be conducted in models of mild SMA wherein disease is primarily driven by dysfunction in the motor unit. It is not unreasonable to suggest that this sort of work could rapidly assume broad relevance, informing not just the biology and treatment of SMA but also other neurodegenerative conditions.
Original Article
Emerging concepts underlying selective neuromuscular dysfunction in infantile-onset spinal muscular atrophy
Neural Regeneration Research
Gollapalli, Kishore; Kim, Jeong-Ki; Monani, Umrao R. PhD
Abstract
Infantile-onset spinal muscular atrophy is the quintessential example of a disorder characterized by a predominantly neurodegenerative phenotype that nevertheless stems from perturbations in a housekeeping protein. Resulting from low levels of the Survival of Motor Neuron (SMN) protein, spinal muscular atrophy manifests mainly as a lower motor neuron disease. Why this is so and whether other cell types contribute to the classic spinal muscular atrophy phenotype continue to be the subject of intense investigation and are only now gaining appreciation. Yet, what is emerging is sometimes as puzzling as it is instructive, arguing for a careful re-examination of recent study outcomes, raising questions about established dogma in the field and making the case for a greater focus on milder spinal muscular atrophy models as tools to identify key mechanisms driving selective neuromuscular dysfunction in the disease. This review examines the evidence for novel molecular and cellular mechanisms that have recently been implicated in spinal muscular atrophy, highlights breakthroughs, points out caveats and poses questions that ought to serve as the basis of new investigations to better understand and treat this and other more common neurodegenerative disorders.
Acknowledgments:
We thank members of the Monani lab for their comments and suggestions for the manuscript.
