A macaque model of Motor Neurone Disease

Abstract

Motor Neurone Disease (MND) is a rapidly progressive and ultimately fatal neurodegenerative disease, characterised by the loss of upper and lower motor neurons. The primary proteinopathy found in approximately 97% of all cases involves cytoplasmic mislocalisation and aggregation of the ubiquitous nuclear protein, TDP-43. Despite the identification of many implicated genes during the last few decades, our understanding of the mechanisms involved in the onset and propagation of pathology have advanced very little. Translatable advancements have likely been limited due a lack of reliable animal models which accurately recapitulate this complex disorder. No model has been created to date which replicates the progressive motor weakness; characteristic histopathologies; extended presymptomatic phase and subsequent rapid deterioration. Rodents have been the dominant species in MND research; however, their anatomy and genetic profile differs fundamentally to humans. Crucially, they lack the direct monosynaptic connection between the upper and lower motor neurons, unique to primates. We have harnessed a novel intersectional genetics approach to induce the overexpression of the human TDP-43 protein in a selective spinal motoneuron population in two Rhesus macaques. This caused to a focal denervation event in the targeted muscle, followed by signs of ongoing denervation and reinnervation in other muscles. In vivo monitoring techniques were selected based on their clinical applications and their ease of use and adaptation for primate research. Comparable sequences of change were detected using MRI, EMG and nerve stimulation, providing compelling evidence for a shared MND-like pathogenesis occurring in both animals. Focal overexpression of TDP-43 in a spinal motor pool was sufficient to induce the expression of pathological phosphorylated TDP-43 throughout the cervical spine and motor cortex. The detection of this histopathology in the distant giant cells of Betz in the primary motor cortex supports the idea of an axon mediated ‘prion-like’ spread, likely involving the corticospinal tract