T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease

Gregory P. Williams, David J. Marmion, Aubrey M. Schonhoff, Asta Jurkuvenaite, Woong Jai Won, David G. Standaert, Jeffrey H. Kordower, Ashley S. Harms

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by abnormal accumulation of alpha-synuclein (α-syn) in oligodendrocytes accompanied by inflammation, demyelination, and subsequent synapse and neuronal loss. Little is known about the mechanisms of neurodegeneration in MSA. However, recent work has highlighted the important role of the immune system to the pathophysiology of other synuclein-related diseases such as Parkinson’s disease. In this study, we investigated postmortem brain tissue from MSA patients and control subjects for evidence of immune activation in the brain. We found a significant increase of HLA-DR+ microglia in the putamen and substantia nigra of MSA patient tissue compared to controls, as well as significant increases in CD3+, CD4+, and CD8+ T cells in these same brain regions. To model MSA in vivo, we utilized a viral vector that selectively overexpresses α-syn in oligodendrocytes (Olig001-SYN) with > 95% tropism in the dorsal striatum of mice, resulting in demyelination and neuroinflammation similar to that observed in human MSA. Oligodendrocyte transduction with this vector resulted in a robust inflammatory response, which included increased MHCII expression on central nervous system (CNS) resident microglia, and infiltration of pro-inflammatory monocytes into the CNS. We also observed robust infiltration of CD4 T cells into the CNS and antigen-experienced CD4 T cells in the draining cervical lymph nodes. Importantly, genetic deletion of TCR-β or CD4 T cells attenuated α-syn-induced inflammation and demyelination in vivo. These results suggest that T cell priming and infiltration into the CNS are key mechanisms of disease pathogenesis in MSA, and therapeutics targeting T cells may be disease modifying.

Original languageEnglish (US)
Pages (from-to)855-874
Number of pages20
JournalActa Neuropathologica
Volume139
Issue number5
DOIs
StatePublished - May 1 2020
Externally publishedYes

Keywords

  • Alpha-synuclein
  • Demyelination
  • Microglia
  • Monocytes
  • Multiple system atrophy
  • Oligodendrocytes
  • T cells

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Fingerprint

Dive into the research topics of 'T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease'. Together they form a unique fingerprint.

Cite this