Decoding inflammatory pathways in spinal muscular atrophy: implications for next-generation therapies.

Spinal muscular atrophy (SMA) is a devastating neurodegenerative disorder caused by SMN1 gene mutations that lead to compromised production of survival motor neuron (SMN) protein. The inflammatory footprint of SMA extends beyond neural tissues, leading to significant inflammatory manifestations across multiple body systems. In motor neurons, several molecular pathways contribute to local degeneration: cytokine activation, purinergic signalling, NF-κB pathway stimulation, complement cascade activation, and glutamate excitotoxicity. These mechanisms, which involve reactive glial and immune cells, trigger neuroinflammation and non-cell-autonomous death processes that can affect non-neural organ systems. Biological samples from patients with SMA and model systems of SMA consistently exhibit altered immune patterns, elevated inflammatory markers, and immunocyte and glial dysfunction. Even revolutionary SMN-restoring therapy for SMA may not treat the potential inflammation-related aspects of the disease. Current research has identified both anti-inflammatory and pro-inflammatory effects and outcomes after SMN restoration, with unclear implications. Preclinical investigations targeting inflammation in SMA models have yielded promising findings, although optimal intervention timing requires refinement. Despite these encouraging results, translation to clinical practice remains unrealized. The field requires advanced investigative approaches, particularly single-cell RNA sequencing, to elucidate inflammatory molecular pathways, identify novel biomarkers for early detection, and develop targeted anti-inflammatory agents that complement SMN-augmenting therapies. Understanding the inflammatory mechanisms associated with SMA is crucial for developing effective combination therapies addressing both SMN deficiency and inflammatory processes. Elucidating inflammation timing and mechanisms will inform optimal intervention windows and identify patients most likely to benefit from combined treatment approaches. Future research should prioritize personalized strategies targeting both SMN-dependent and inflammatory pathways.