Endogenous SMN Heterogeneity Defines Dynamic States of Motor Neuron Vulnerability and Resilience

Selective neuronal vulnerability, a hallmark of neurodegenerative diseases, is defined by certain neurons degenerating while others remain resilient despite shared genetic and disease contexts. The intrinsic mechanisms behind these divergent fates are yet to be fully understood. In a recent study, researchers have identified naturally occurring heterogeneity in the endogenous Survival Motor Neuron (SMN) protein abundance as a key factor in motor neuron (MN) vulnerability states that predict neuronal fate.

Using live-cell imaging of human SMN-Clover reporter MNs, the team observed that neurons with higher endogenous SMN levels survive significantly longer than neighboring neurons with lower SMN levels, regardless of the genetic background, whether healthy, spinal muscular atrophy (SMA), or amyotrophic lateral sclerosis (ALS). These vulnerability states are not static; a substantial proportion of MNs gradually increase their endogenous SMN abundance, transitioning into a more resilient state characterized by enhanced survival.

Notably, low-SMN neurons also exhibit increased spontaneous activity, suggesting a link between SMN abundance, neuronal physiology, and survival. In live animals, vulnerable MN populations demonstrate corresponding shifts in endogenous SMN abundance as the disease progresses, highlighting the relevance of SMN-defined vulnerability states beyond in vitro models.

Comprehensive transcriptomic and proteomic analyses revealed distinct molecular programs associated with resilient and vulnerable states, encompassing RNA metabolism, proteostasis, cytoskeletal organization, neuronal activity, and stress responses. Among the conserved molecular differences, the anti-apoptotic regulator LMO3 emerged as a potential mediator of resilience.

Enhancing LMO3 levels reduced p53-responsive gene expression, increased MN survival, and shifted neurons toward higher endogenous SMN states. Overall, these findings establish endogenous protein heterogeneity as a determinant of dynamic neuronal vulnerability and uncover neuronal resilience as a plastic molecular state that can be identified and potentially therapeutically exploited.