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

Mechanisms underlying α-synuclein (αSyn) mediated neurodegeneration are poorly understood. Intramuscular (IM) injection of αSyn fibrils in human A53T transgenic M83+/− mice produce a rapid model of α-synucleinopathy with highly predictable onset of motor impairment. Using varying doses of αSyn seeds, we show that αSyn-induced phenotype is largely dose-independent. We utilized the synchrony of this IM model to explore the temporal sequence of αSyn pathology, neurodegeneration and neuroinflammation. Longitudinal tracking showed that while motor neuron death and αSyn 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 insights into the role of neuroinflammation in αSyn mediated proteostasis and neurodegeneration, which will be key in designing potential therapies. [Display omitted] •Aggregated α-synuclein (αSyn), inflammation and neurodegeneration characterize α-synucleinopathies.•Peripheral to central transmission of αSyn resulting in paralysis is independent of αSyn dose.•Motor neuron death, αSyn pathology and neuroinflammation follow distinct temporal profiles.•Endstage αSyn pathology is characterized by an overwhelming immune response.