1. Motor neuron loss and neuroinflammation in a model of α-synuclein-induced neurodegeneration.
- Author
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Sorrentino ZA, Xia Y, Funk C, Riffe CJ, Rutherford NJ, Ceballos Diaz C, Sacino AN, Price ND, Golde TE, Giasson BI, and Chakrabarty P
- Subjects
- Animals, Brain immunology, Brain metabolism, Brain pathology, Female, Humans, Inflammation immunology, Inflammation metabolism, Inflammation pathology, Male, Mice, Mice, Transgenic, Motor Neurons immunology, Motor Neurons pathology, Nerve Degeneration immunology, Nerve Degeneration pathology, Spinal Cord immunology, Spinal Cord metabolism, Spinal Cord pathology, alpha-Synuclein immunology, Motor Neurons metabolism, Nerve Degeneration metabolism, alpha-Synuclein biosynthesis
- Abstract
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., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2018
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