Editors' ChoiceParkinson’s Disease

Microglia seeding the brain for α-synuclein pathology

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Science Translational Medicine  12 Jun 2019:
Vol. 11, Issue 496, eaax9563
DOI: 10.1126/scitranslmed.aax9563

Abstract

The prion-like mechanism for spreading α-synuclein pathology may be facilitated by microgliosis in Parkinson’s disease.

The hierarchical pattern of α-synuclein pathology in Parkinson’s disease (PD) is consistent with the phenomenon of “spreading” α-synuclein aggregates from cell to cell. Some of the earliest evidence for spreading α-synuclein pathology came from postmortem studies following the transplantation of fetal mesencephalic tissue into the brains of advanced PD patients. Examination of the longest surviving PD patient 14 years after transplantation revealed that embryonic dopamine neurons displayed α-synuclein aggregates. This study led to the speculation that the diseased brain environment enabled the transmission of α-synuclein pathology into otherwise healthy implanted neurons.

To better understand this “prion-like” phenomenon of α-synuclein spreading, Warren et al. investigated the temporal relationship between α-synuclein pathology and inflammation. By examining the brains from PD patients at 18 months, 4, 14, and 16 years following transplantation surgeries, the authors first revealed an abundant of surviving grafted embryonic neurons in all patients. Histopathological analyses at the earliest time point demonstrated that the grafted embryonic neurons were devoid of α-synuclein protein and only soluble, nonaggregated proteinase K-digestible α-synuclein was evident at 4 years posttransplantation. At later time points, embryonic neurons displayed α-synuclein pathology consisting of ubiquitin-positive phosphorylated Ser129-synuclein that were proteinase K resistant. In contrast, histological analysis demonstrated an exacerbated microglia response within grafted regions at all time points, with the appearance of higher intensity at 16 years posttransplantation. Morphologically, the microglia displayed dense swollen and short processes with enlarged cell bodies that differed from the small microglial cell bodies and long ramified processes found in healthy brains.

The presence and distinct morphology of microglia before α-synuclein pathology suggest they potentially prime the diseased brain, facilitating the spread of α-synuclein pathology. In future studies, it will be imperative to decipher whether microglia directly impact neuronal health, increasing their vulnerability for the transmission of α-synuclein aggregates, or whether microglia directly aid in the transmission of α-synuclein aggregates. Moreover, it will be essential to investigate the temporal relationship between reactive astrocytes and α-synuclein pathology and to consider the surgical procedure itself as an initiating factor, as the authors also detected the presence of leukocyte common antigen (CD45)–positive cells, which is suggestive of macrophage infiltration.

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