A non-human primate model of Amyotrophic Lateral Sclerosis

Abstract

Approximately 97% of patients with amyotrophic lateral sclerosis (ALS) have cytoplasmic mislocalization and aggregation of the ubiquitous nuclear protein, TDP-43. Current rodent models of this disease fail to replicate the progressive motor weakness and characteristic histopathology, possibly because of fundamental neuroanatomical and genetic differences between rodents and humans. In this study, the TDP-43 protein was overexpressed in the motor neuron pool of the brachioradialis muscle unilaterally in two six-year-old female rhesus macaques, using an intersectional genetics approach involving infection with genetically modified adeno-associated virus. Magnetic resonance images demonstrated delayed signal hyperintensities limited to the injected brachioradialis that persisted for 6-7 weeks, consistent with motor neuron degeneration and denervation of the targeted muscle. At post-mortem, the virus-mediated focal protein overexpression event was found to induce widespread deposits of pathological phosphorylated TDP-43 throughout the cervical spinal cord and motor cortex bilaterally, indicating an ALS-like spread of proteinopathy from the transfection site.