Identification and Quantification of Oligodendrocyte Precursor Cells in Multiple System Atrophy, Progressive Supranuclear Palsy and Parkinson's Disease

Abstract

Multiple system atrophy is a neurodegenerative disorder characterized pathologically by abnormal accumulations of α-synuclein in the cytoplasm of oligodendrocytes, which are termed glial cytoplasmic inclusions (GCIs). Oligodendrocytes are responsible for myelinating axons and providing neurotrophic support, but in MSA, myelin loss, axonal loss and gliosis are consistent features suggesting that GCIs play a central role in disease pathogenesis. Oligodendroglial, myelin and axonal degeneration are also features of multiple sclerosis (MS) in which recent studies have highlighted the robust remyelination capacity of the central nervous system (CNS). The cells responsible for remyelination are called oligodendroglial precursor cells (OPCs). In this study, we investigated the role of OPCs in the pathogenesis of MSA and progressive supranuclear palsy (PSP), a neurodegenerative disease in which neuropathological changes include oligodendroglial inclusions composed of microtubule-associated protein tau. Despite the lability of OPC-specific antigens, we successfully identified OPCs and demonstrated that tau and α-synuclein do not accumulate in OPCs. We also showed that the density of OPCs was increased in a white matter region of the MSA brain, which is also severely affected by GCIs and myelin degeneration. These findings raise the possibility that OPCs could be available to repair disease-associated damage in MSA, consistent with their biological function.

Promoting oligodendrocyte progenitor cell maturation and remyelination as a novel therapeutical approach for multiple system atrophy

“…Applying a bromodeoxyuridine (BrdU) based fate mapping, increased numbers of newborn striatal OPCs were detected in MBP::aSyn mice compared to non-transgenic littermates while numbers of glutathione-s-transferase-pi (GSTpi)-positive OLGs were unaffected. Further analyzing MSA post-mortem tissue and in contrast to previous reports, we detected a small fraction (5-8%) of aSyn-positive striatal OPCs indicating that aSyn accumulation is not restricted to mature OLGs but also affects OPCs [1,18] .…”

“…Intriguingly, we observed increased numbers of striatal platelet-derived growth factor receptor-alpha (PDGFRa)-positive OPCs in MSA patients suggesting a proliferative reaction of OPCs in response to demyelination in MSA [1] . Similar results have been obtained by Ahmed and colleagues analyzing cerebellar white matter of MSA patients [18] . In line with these observations, we detected increased numbers of proliferative OPCs in transgenic mice expressing aSyn under the control of the OLG specific myelin basic protein (MBP)-promoter (MBP::aSyn) [1] .…”

Neuroimaging evidence of gray and white matter damage and clinical correlates in progressive supranuclear palsy

“…An alternative hypothesis is that the lack of spatial correlation between GM and WM in PSP is due to mechanisms of remyelination. Oligodendrocyte precursor cells, which are present in the brain of patients with PSP [42], may play a role in remyelination by participating in repair disease processes. By contrast, there is no evidence of restorative processes involving the GM in PSP.…”

The Role of NO/cGMP Signaling on Neuroinflammation: A New Therapeutic Opportunity

“…Oligodendrocyte dysfunction and myelin abnormalities are found in a wide variety of neurological diseases and may be involved in the pathophysiology of various diseases, including genetic leukodystrophies [74], schizophrenia and bipolar disorder [75,76], brain injury [77], and endocrine and metabolic abnormalities [78,79] and neurodegenerative conditions such as strokes [80,81], Parkinson's disease [82], Alzheimer's disease [83][84][85], multiple sclerosis [86], and diabetic encephalopathy [87].…”