Cytoplasmic TDP-43 Accumulation in Autosomal Recessive Spastic Ataxia of Charlevoix–Saguenay

ABSTRACT Background: Autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) is a rare, early-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, spasticity and peripheral neuropathy. It is caused by biallelic mutations in the SACS gene, which encodes sacsin, a large protein involved in cytoskeletal organization and mitochondrial homeostasis, and protein quality control. Despite advances in understanding sacsin biology, the molecular mechanisms underlying neurodegeneration in ARSACS remain incompletely understood. Here, we report the first neuropathological evidence of pathological TAR DNA-binding protein 43 (TDP-43) accumulation in ARSACS. Methods: Available postmortem brain tissue from a genetically confirmed ARSACS patient homozygous for the Quebec founder mutation ( SACS c.8844delT) was analyzed by immunohistochemistry, immunofluorescence and biochemical fractionation. Results: Neurons in the prefrontal cortex, motor cortex and cerebellum exhibited cytoplasmic phosphorylated dot-like TDP-43 (pTDP-43) aggregates with reduced nuclear localization. Biochemical fractionation further identified detergent-insoluble TDP-43 species in ARSACS tissue. Additional pathological features included increased neurofilament accumulation, vacuole-like neuronal changes, Purkinje cell loss and p62-positive cytoplasmic inclusions. Similar dot-like cytoplasmic pTDP-43 aggregates were observed in a second ARSACS case. Conclusion: These findings identify pTDP-43 as a previously unrecognized pathological feature of ARSACS. While the patient exhibited no clinical or histopathological signs of amyotrophic lateral sclerosis, the presence of atypical pTDP-43 aggregates observed in ARSACS may represent a rare, secondary, early-stage or potentially underrecognized manifestation of TDP-43 pathology rather than a defining hallmark of the disease. Further studies in additional patients and experimental ARSACS models will be required to determine the prevalence and mechanistic basis of TDP-43 abnormalities in this disorder.