Immunoregulation of microglial polarization: an unrecognized physiological function of α-synuclein.

BACKGROUND: Microglial function is vital for maintaining the health of the brain, and their activation is an essential component of neurodegeneration. There is significant research on factors that provoke "reactive" or "inflammatory" phenotypes in conditions of injury or disease. One such factor, exposure to the aggregated or oligomeric forms of α-synuclein, an abundant brain protein, plays an essential role in driving microglial activation; including chemotactic migration and production of inflammatory mediators in Lewy body (LB) diseases such as Parkinson's disease. On the other hand, it is increasingly recognized that microglia also undergo changes, dependent on the cellular environment, that promote mainly reconstructive and anti-inflammatory functions, i.e., mostly desirable functions of microglia in a physiological state. What maintains microglia in this physiological state is essentially unknown. METHODS: In this study, using in vitro and in vivo models, we challenged primary microglia or BV2 microglia with LPS + IFN-γ, IL-4 + IL-13, α-synuclein monomer, and α-synuclein oligomer, and examined microglia phenotype and the underlying mechanism by RT-PCR, Western blot, ELISA, IF, IHC, Co-IP. RESULTS: We described a novel physiological function of α-synuclein, in which it modulates microglia toward an anti-inflammatory phenotype by interaction with extracellular signal-regulated kinase (ERK) and recruitment of the ERK, nuclear factor kappa B (NF-κB), and peroxisome proliferator-activated receptor γ (PPARγ) pathways. CONCLUSIONS: These findings suggest a previously unrecognized function of monomeric α-synuclein that likely gives new insights into the pathogenesis and potential therapies for Lewy body-related diseases and beyond, given the abundance and multiple functions of α-synuclein in brain tissue.

Mass spectrometry: A platform for biomarker discovery and validation for Alzheimer's and Parkinson's diseases.

Accurate, reliable, and objective biomarkers for Alzheimer's disease (AD), Parkinson's disease (PD), and related age-associated neurodegenerative disorders are urgently needed to assist in both diagnosis, particularly at early stages, and monitoring of disease progression. Technological advancements in protein detection platforms over the last few decades have resulted in a plethora of reported molecular biomarker candidates for both AD and PD; however, very few of these candidates are developed beyond the discovery phase of the biomarker development pipeline, a reflection of the current bottleneck within the field. In this review, the expanded use of selected reaction monitoring (SRM) targeted mass spectrometry will be discussed in detail as a platform for systematic verification of large panels of protein biomarker candidates prior to costly validation testing. We also advocate for the coupling of discovery-based proteomics with modern targeted MS-based approaches (e.g., SRM) within a single study in future workflows to expedite biomarker development and validation for AD and PD. It is our hope that improving the efficiency within the biomarker development process by use of an SRM pipeline may ultimately hasten the development of biomarkers that both decrease misdiagnosis of AD and PD and ultimately lead to detection at early stages of disease and objective assessment of disease progression. This article is part of the special issue "Proteomics".

Reduced erythrocytic CHCHD2 mRNA is associated with brain pathology of Parkinson's disease.

Peripheral biomarkers indicative of brain pathology are critically needed for early detection of Parkinson's disease (PD). In this study, using NanoString and digital PCR technologies, we began by screening for alterations in genes associated with PD or atypical Parkinsonism in erythrocytes of PD patients, in which PD-related changes have been reported, and which contain ~ 99% of blood α-synuclein. Erythrocytic CHCHD2 mRNA was significantly reduced even at the early stages of the disease. A significant reduction in protein and/or mRNA expression of CHCHD2 was confirmed in PD brains collected at autopsy as well as in the brains of a PD animal model overexpressing α-synuclein, in addition to seeing a reduction of CHCHD2 in erythrocytes of the same animals. Overexpression of α-synuclein in cellular models of PD also resulted in reduced CHCHD2, via mechanisms likely involving altered subcellular localization of p300 histone acetyltransferase. Finally, the utility of reduced CHCHD2 mRNA as a biomarker for detecting PD, including early-stage PD, was validated in a larger cohort of 205 PD patients and 135 normal controls, with a receiver operating characteristic analysis demonstrating > 80% sensitivity and specificity.