With the advent of the genetic era in Parkinson's disease (PD) research in 1997, α-synuclein was identified as an important player in a complex neurodegenerative disease that affects >10 million people worldwide. PD has been estimated to have an economic impact of $51.9 billion in the US alone. Since the initial association with PD, hundreds of researchers have contributed to elucidating the functions of α-synuclein in normal and pathological states, and these remain critical areas for continued research. With this position paper the authors strive to achieve two goals: first, to succinctly summarize the critical features that define α-synuclein's varied roles, as they are known today; and second, to identify the most pressing knowledge gaps and delineate a multipronged strategy for future research with the goal of enabling therapies to stop or slow disease progression in PD.

/pdf/alpha-synuclein-research-defining-strategic-moves-in-the-1py977nwtc.pdf

Alpha-synuclein research: defining strategic moves in the battle against Parkinson’s disease

Alpha synuclein in hematopoiesis and immunity.

Misfolded proteins, inflammation, and vascular alterations are common pathological hallmarks of neurodegenerative diseases. Alpha-synuclein is a small synaptic protein that was identified as a major component of Lewy bodies and Lewy neurites in the brain of patients affected by Parkinson's disease (PD), Lewy body dementia (LBD), and other synucleinopathies. It is mainly involved in the regulation of synaptic vesicle trafficking but can also control mitochondrial/endoplasmic reticulum (ER) homeostasis, lysosome/phagosome function, and cytoskeleton organization. Recent evidence supports that the pathological forms of α-synuclein can also reduce the release of vasoactive and inflammatory mediators from endothelial cells (ECs) and modulates the expression of tight junction (TJ) proteins important for maintaining the blood-brain barrier (BBB). This hints that α-synuclein deposition can affect BBB integrity. Border associated macrophages (BAMs) are brain resident macrophages found in association with the vasculature (PVMs), meninges (MAMs), and choroid plexus (CPMs). Recent findings indicate that these cells play distinct roles in stroke and neurodegenerative disorders. Although many studies have addressed how α-synuclein may modulate microglia, its effect on BAMs has been scarcely investigated. This review aims at summarizing the main findings supporting how α-synuclein can affect ECs and/or BAMs function as well as their interplay and effect on other cells in the brain perivascular environment in physiological and pathological conditions. Gaps of knowledge and new perspectives on how this protein can contribute to neurodegeneration by inducing BBB homeostatic changes in different neurological conditions are highlighted.

/pdf/alpha-synuclein-in-the-regulation-of-brain-endothelial-and-xvp8glxmiz.pdf

Alpha-Synuclein in the Regulation of Brain Endothelial and Perivascular Cells: Gaps and Future Perspectives.

Central nervous system (CNS) accumulation of fibrillary deposits made of Amyloid β (Aβ), hyperphosphorylated Tau or α-synuclein (α-syn), present either alone or in the form of mixed pathology, characterizes the most common neurodegenerative diseases (NDDs) as well as the aging brain. Compelling evidence supports that acute neurological disorders, such as traumatic brain injury (TBI) and stroke, are also accompanied by increased deposition of toxic Aβ, Tau and α-syn species. While the contribution of these pathological proteins to neurodegeneration has been experimentally ascertained, the cellular and molecular mechanisms driving Aβ, Tau and α-syn-related brain damage remain to be fully clarified. In the last few years, studies have shown that Aβ, Tau and α-syn may contribute to neurodegeneration also by inducing and/or promoting blood-brain barrier (BBB) disruption. These pathological proteins can affect BBB integrity either directly by affecting key BBB components such as pericytes and endothelial cells (ECs) or indirectly, by promoting brain macrophages activation and dysfunction. Here, we summarize and critically discuss key findings showing how Aβ, Tau and α-syn can contribute to BBB damage in most common NDDs, TBI and stroke. We also highlight the need for a deeper characterization of the role of these pathological proteins in the activation and dysfunction of brain macrophages, pericytes and ECs to improve diagnosis and treatment of acute and chronic neurological disorders. 

The contribution of β-amyloid, Tau and α-synuclein to blood–brain barrier damage in neurodegenerative disorders

The etiology of Parkinson's disease is poorly understood and is most commonly associated with advancing age, genetic predisposition, or environmental toxins. Epidemiological findings suggest that patients have a higher risk of developing Parkinson's disease after ischemic stroke, but this potential causality lacks mechanistic evidence. We investigated the long-term effects of ischemic stroke on pathogenesis in hemizygous TgM83 mice, which express human α-synuclein with the familial A53T mutation without developing any neuropathology or signs of neurologic disease for more than 600 days. We induced transient focal ischemia by middle cerebral artery occlusion in 2-month-old TgM83+/- mice and monitored their behavior and health status for up to 360 days post surgery. Groups of mice were sacrificed at 14, 30, 90, 180, and 360 days after surgery for neuropathological analysis of their brains. Motor deficits first appeared 6 months after focal ischemia and worsened until 12 months afterward. Immunohistochemical analysis revealed ischemia-induced neuronal loss in the infarct region and astrogliosis and microgliosis indicative of an inflammatory response, which was most pronounced at 14 days post surgery. Infarct volume and inflammation gradually decreased in size and severity until 180 days post surgery. Surprisingly, neuronal loss and inflammation were increased again by 360 days post surgery. These changes were accompanied by a continuous increase in α-synuclein aggregation, its neuronal deposition, and a late loss of dopaminergic neurons in the substantia nigra, which we detected at 360 days post surgery. Control animals that underwent sham surgery without middle cerebral artery occlusion showed no signs of disease or neuropathology. Our results establish a mechanistic link between ischemic stroke and Parkinson's disease and provide an animal model for studying possible interventions. 

/pdf/ischemic-stroke-causes-parkinsons-disease-like-pathology-and-2lyv9ebj.pdf

Ischemic stroke causes Parkinson’s disease-like pathology and symptoms in transgenic mice overexpressing alpha-synuclein

Post-stroke induction of alpha-synuclein (AS), a neuronal protein implicated in the pathogenesis of Parkinson's disease (PD), has been demonstrated to induce secondary brain damage after cerebral ischemia. Therefore, understanding the expression and pathogenic modifications of AS is clinically meaningful for evaluating the prognosis of stroke. Here, 54 patients with acute ischemic stroke (AIS) and 55 controls were enrolled. Different forms of AS in red blood cells (RBCs), including hemoglobin-bound AS (Hb-AS), oligomeric AS (O-AS), and serine 129-phosphorylated AS (pS-AS), were measured using ELISA methods. Compared with controls, significantly increased levels of Hb-AS, O-AS, and pS-AS were observed in AIS patients. The levels of O-AS and pS-AS were both positively correlated with that of Hb-AS. However, no correlation was observed between O-AS and pS-AS. The levels of all three forms of AS were associated with increased risk of AIS diagnosis. Receiver operating characteristic (ROC) curves revealed that the three forms of AS yielded a moderate discriminative power (AUC ranging from 0.67 to 0.71 in discriminating AIS patients from controls, with varying sensitivity (0.41~0.61), specificity (0.78~0.90), PPV (0.73~0.81), and NPV (0.61~0.68)). These findings suggest that RBC AS can be a potential biomarker for evaluating AS changes in the brain of AIS patients.

Alpha-synuclein alterations in red blood cells of peripheral blood after acute ischemic stroke.

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Alpha-synuclein alterations in red blood cells of peripheral blood after acute ischemic stroke.