Journal
ACTA NEUROPATHOLOGICA
Volume 139, Issue 5, Pages 855-874Publisher
SPRINGER
DOI: 10.1007/s00401-020-02126-w
Keywords
Multiple system atrophy; T cells; Demyelination; Oligodendrocytes; Microglia; Monocytes; Alpha-synuclein
Categories
Funding
- NIH/NINDS [R01NS107316]
- National Institute of Neurological Disorders and Stroke (National Brain and Tissue Resource for Parkinson's Disease and Related Disorders) [U24 NS 072026]
- National Institute on Aging (Arizona Alzheimer's Disease Core Center) [P30 AG19610]
- Arizona Biomedical Research Commission [4001, 0011, 05-901, 1001]
- Michael J. Fox Foundation for Parkinson's Research
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [F31NS106820, F31NS106722] Funding Source: NIH RePORTER
Ask authors/readers for more resources
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by abnormal accumulation of alpha-synuclein (alpha-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 alpha-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-beta or CD4 T cells attenuated alpha-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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available