Non-Cell-Autonomous Mechanisms and Systemic Interactions in Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is an inherited neurodegenerative disorder caused by a deficiency of the survival motor neuron (SMN) protein. Traditionally, it has been classified as a motor neuron disease. Over the past decade, however, numerous nonmotor neuronal and nonneural pathologies reported in both patients with SMA and mouse models have led to its redefinition as a systemic disorder. Although SMN protein expression outside the central nervous system is well established, it remains controversial whether its functional loss in nonneuronal cells/tissues merely represents a comorbidity or actively contributes to driving motor neuron degeneration. This review summarizes key evidence supporting the non-cell-autonomous death of motor neurons in SMA. On the basis of these lines of evidence, three potential pathways for pathologic transmission are proposed: i) neuroinflammatory and neurotoxicity signaling mediated by glial cells, ii) aberrant retrograde signaling from the neuromuscular junction, and iii) modulation of the central nervous system by peripheral factors via the circulatory system. Future studies should focus on identifying critical peripheral tissues involved in SMA pathogenesis, elucidating the molecular mechanisms by which SMN deficiency leads to dysfunction in these tissues, and characterizing key mediators that influence motor neuron survival. In the current era where SMN-enhancing therapies have significantly improved patient survival, a deeper understanding of non-cell-autonomous mechanisms, and targeting them, represents a crucial step toward achieving curative strategies for SMA.