Neuroaxonal Degeneration as a Converging Mechanism in Motor Neuron Diseases (MNDs): Molecular Insights into RNA Dysregulation and Emerging Therapeutic Targets

Abstract

Motor Neuron Diseases (MNDs) such as Amyotrophic Lateral Sclerosis (ALS), Primary Lateral Sclerosis (PLS), Hereditary Spastic Paraplegia (HSP), Spinal Muscular Atrophy with Respiratory Distress Type 1 (SMARD1), Multisystem Proteinopathy (MSP), Spinal and Bulbar Muscular Atrophy (SBMA), and ALS associated to Frontotemporal Dementia (ALS-FTD), have traditionally been studied as distinct entities, each one with unique genetic and clinical characteristics. However, emerging research reveals that these seemingly disparate conditions converge on shared molecular mechanisms that drive progressive neuroaxonal degeneration. This narrative review addresses a critical gap in the field by synthesizing the most recent findings into a comprehensive, cross-disease mechanisms framework. By integrating insights into RNA dysregulation, protein misfolding, mitochondrial dysfunction, DNA damage, kinase signaling, axonal transport failure, and immune activation, we highlight how these converging pathways create a common pathogenic landscape across MNDs. Importantly, this perspective not only reframes MNDs as interconnected neurodegenerative models but also identifies shared therapeutic targets and emerging strategies, including antisense oligonucleotides, autophagy modulators, kinase inhibitors, and immunotherapies that transcend individual disease boundaries. The diagnostic and prognostic potential of Neurofilament Light Chain (NfL) biomarkers is also emphasized. By shifting focus from gene-specific to mechanism-based approaches, this paper offers a much-needed roadmap for advancing both research and clinical management in MNDs, paving the way for cross-disease therapeutic innovations.

Keywords: DNA repair; RNA-binding proteins; axonal transport; kinase signaling; mitochondrial dysfunction; motor neuron diseases; neurofilament biomarkers; neuroinflammation; protein aggregation; targeted therapies.

Figure 1

Common molecular mechanisms driving neuroaxonal degeneration within MNDs. Note: Key pathogenic pathways, including RNA dysregulation, protein aggregation, mitochondrial dysfunction, axonal transport defects, DNA damage, and immune activation, converge on neuroaxonal degeneration across ALS/ALS-FTD, PLS, SMA, SBMA, HSP, PCH1, MSP, IBMPFD, and SMARD1.

Figure 2

RNA dysregulation in motor neuron diseases: mechanisms and therapeutic targets. Note: Mutations in RNA-binding proteins (TARDBP, FUS, C9orf72, SMN1/2, IGHMBP2, EXOSC3, VCP, ATXN2) lead to their mislocalization, resulting in impaired splicing, RNA foci, stress granules, and R-loop formation. These disruptions impair mRNA transport and translation, contribute to toxic dipeptide repeat protein production, and culminate in axonal dysfunction. Therapeutic approaches include ASOs and gene-editing strategies targeting RNA metabolism.