Motor neuron loss and neuroinflammation in a model of α-synuclein-induced neurodegeneration

Mechanisms underlying alpha-synuclein (alpha Syn) mediated neurodegeneration are poorly understood. Intramuscular (IM) injection of alpha Syn fibrils in human A53T transgenic M83(+/-) mice produce a rapid model of alpha-synucleinopathy with highly predictable onset of motor impairment. Using varying doses of alpha Syn seeds, we show that alpha Syn-induced phenotype is largely dose-independent. We utilized the synchrony of this IM model to explore the temporal sequence of alpha Syn pathology, neurodegeneration and neuroinflammation. Longitudinal tracking showed that while motor neuron death and alpha Syn pathology occur within 2 months post IM, astrogliosis appears at a later timepoint, implying neuroinflammation is a consequence, rather than a trigger, in this prionoid model of synucleinopathy. Initiating at 3 months post IM, immune activation dominates the pathologic landscape in terminal IM-seeded M83(+/-) mice, as revealed by unbiased transcriptomic analyses. Our findings provide in- sights into the role of neuroinflammation in alpha Syn mediated proteostasis and neurodegeneration, which will be key in designing potential therapies.