TY - JOUR
T1 - Motor neuron loss and neuroinflammation in a model of α-synuclein-induced neurodegeneration
AU - Sorrentino, Zachary A.
AU - Xia, Yuxing
AU - Funk, Cory
AU - Riffe, Cara J.
AU - Rutherford, Nicola J.
AU - Ceballos Diaz, Carolina
AU - Sacino, Amanda N.
AU - Price, Nathan D.
AU - Golde, Todd E.
AU - Giasson, Benoit I.
AU - Chakrabarty, Paramita
N1 - Publisher Copyright:
© 2018
PY - 2018/12
Y1 - 2018/12
N2 - 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.
AB - 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.
KW - Inflammation
KW - Neurodegeneration
KW - Prionoid transmission
KW - RNAseq
KW - α-synuclein
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UR - http://www.scopus.com/inward/citedby.url?scp=85053175315&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2018.09.005
DO - 10.1016/j.nbd.2018.09.005
M3 - Article
C2 - 30195075
AN - SCOPUS:85053175315
SN - 0969-9961
VL - 120
SP - 98
EP - 106
JO - Neurobiology of Disease
JF - Neurobiology of Disease
ER -