Rodent Models of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder characterized by the selective loss of upper and lower motor neurons. Clinically, it manifests as muscle weakness, spasticity, dysphagia, and ultimately paralysis. While the majority of ALS cases are sporadic, approximately 10% are familial, commonly associated with mutations in genes such as SOD1 , TARDBP , FUS , and C9orf72 . The frequent clinical and pathological overlap with frontotemporal dementia (FTD) has led to the reclassification of ALS as a multisystem neurodegenerative disease. Rodent models have been instrumental in unraveling ALS pathogenesis and testing experimental therapeutics. This chapter reviews key pathological features of ALS and provides an overview of both genetic and non-genetic rodent models. Among the genetic models, transgenic rodents expressing mutant forms of SOD1 , TDP-43 , FUS , or C9orf72 exhibit progressive motor deficits, neuroinflammation, and proteinopathy that closely mimic human ALS pathology. Other models based on mutations in ALS2 , OPTN , UBQLN2 , PFN1 , VCP , and VAPB are also covered, highlighting the diverse genetic landscape of ALS. In addition to genetic models, environmental exposure models such as those using β-N-methylamino-L-alanine (L-BMAA)—a cyanobacterial neurotoxin—are discussed. Chronic L-BMAA exposure in rodents induces motor neuron degeneration, glutamate excitotoxicity, and TDP-43 mislocalization, providing a non-genetic platform to study sporadic ALS and the role of environmental risk factors. While no single model recapitulates all disease features, each offers unique insights into specific mechanisms. This chapter aims to support researchers in selecting appropriate rodent models for mechanistic and translational ALS research, bridging the gap between basic science and therapeutic development.