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

Zachary A. Sorrentino; Yuxing Xia; Cory Funk; Cara J. Riffe; Nicola J. Rutherford; Carolina Ceballos Diaz; Amanda N. Sacino; Nathan D. Price; Todd E. Golde; Benoit I. Giasson; Paramita Chakrabarty

Neurobiology of Disease (Dec 2018)

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

Zachary A. Sorrentino,
Yuxing Xia,
Cory Funk,
Cara J. Riffe,
Nicola J. Rutherford,
Carolina Ceballos Diaz,
Amanda N. Sacino,
Nathan D. Price,
Todd E. Golde,
Benoit I. Giasson,
Paramita Chakrabarty

Affiliations

Zachary A. Sorrentino: Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32610, USA
Yuxing Xia: Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32610, USA
Cory Funk: Institute of Systems Biology, Seattle, WA 98109, USA
Cara J. Riffe: Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32610, USA
Nicola J. Rutherford: Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32610, USA
Carolina Ceballos Diaz: Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32610, USA
Amanda N. Sacino: Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32610, USA
Nathan D. Price: Institute of Systems Biology, Seattle, WA 98109, USA
Todd E. Golde: Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA
Benoit I. Giasson: Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA; Corresponding authors at: Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA.
Paramita Chakrabarty: Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA; Corresponding authors at: Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA.

Journal volume & issue: Vol. 120
pp. 98 – 106

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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