Selective Neuroprotection in the ALS-FTD Spectrum: Mechanisms of Neuronal Resilience and Translational Perspectives

Amyotrophic lateral sclerosis (ALS) is increasingly recognized as part of a broader clinico-pathological continuum encompassing frontotemporal dementia (FTD). Despite progressive degeneration across motor and cognitive neural systems associated with TDP-43 pathology, specific neuronal populations-including the oculomotor and abducens nuclei, Onuf's nucleus, and sensory dorsal column pathways-remain relatively preserved.

Selectively preserved neuronal structures in ALS have largely been described as isolated neuropathological observations without sufficient mechanistic integration. This review aims to synthesize candidate intrinsic and microenvironmental mechanisms that may contribute to selective neuronal preservation and propose a translational framework for understanding neuronal resilience in the ALS-FTD spectrum.

We conducted a comprehensive critical review of the literature addressing selective neuronal vulnerability and resistance in ALS-FTD, integrating comparative observations from related neurodegenerative and neuromuscular disorders. Particular emphasis was placed on candidate mechanisms associated with neuronal resilience, including Nrf2/ARE signaling, calcium homeostasis, glutamatergic receptor composition, glial-mediated neurotrophic support, and emerging transcriptomic evidence relevant to selective neuronal vulnerability.

Selective preservation of specific neuronal populations represents a distinctive biological characteristic of the ALS-FTD spectrum. Current evidence suggests that enhanced antioxidant defense, tightly regulated intracellular calcium dynamics, protective microenvironmental interactions, and other stress-response pathways may collectively contribute to resistance against TDP-43 proteinopathy. These findings may provide a mechanistic framework for understanding selective neuronal resilience and suggest potential avenues for future neuroprotective therapeutic development.

Integrating mechanisms of selective neuroprotection with translational neurobiological perspectives may provide a conceptual framework for ALS research. Leveraging preserved neural systems may not only inform biologically grounded supportive care strategies but also help identify mechanistically relevant targets for future disease-modifying interventions.