Revisiting Alpha-Synuclein Pathways to Inflammation

PLoS ONE, 2013

Alpha-synuclein protein is strongly implicated in the pathogenesis Parkinson's disease. Increased expression of a-synuclein due to genetic multiplication or point mutations leads to early onset disease. While a-synuclein is known to modulate membrane vesicle dynamics, it is not clear if this activity is involved in the pathogenic process or if measurable physiological effects of a-synuclein over-expression or mutation exist in vivo. Macrophages and microglia isolated from BAC a-synuclein transgenic mice, which overexpress a-synuclein under regulation of its own promoter, express a-synuclein and exhibit impaired cytokine release and phagocytosis. These processes were affected in vivo as well, both in peritoneal macrophages and microglia in the CNS. Extending these findings to humans, we found similar results with monocytes and fibroblasts isolated from idiopathic or familial Parkinson's disease patients compared to age-matched controls. In summary, this paper provides 1) a new animal model to measure a-synuclein dysfunction; 2) a cellular system to measure synchronized mobilization of a-synuclein and its functional interactions; 3) observations regarding a potential role for innate immune cell function in the development and progression of Parkinson's disease and other human synucleinopathies; 4) putative peripheral biomarkers to study and track these processes in human subjects. While altered neuronal function is a primary issue in PD, the widespread consequence of abnormal a-synuclein expression in other cell types, including immune cells, could play an important role in the neurodegenerative progression of PD and other synucleinopathies. Moreover, increased a-synuclein and altered phagocytosis may provide a useful biomarker for human PD. PLOS ONE | www.plosone.org August 2013 | Volume 8 | Issue 8 | e71634 a-Syn Impedes Innate Immune Activity PLOS ONE | www.plosone.org 2 August 2013 | Volume 8 | Issue 8 | e71634

2020

Since Braak’s hypothesis stating that sporadic Parkinson’s disease follows a specific progression of the pathology from the peripheral to the central nervous system and can be monitored by detecting accumulation of the alpha-Synuclein protein. There is growing interest in understanding how the gut (commensal) microbiome can regulate alpha-Synuclein accumulation which can lead to PD. We studied a transgenic rat model overexpressing the human alpha-Synuclein and found that the protein overexpression resulted in gut alpha-Synuclein expression and aggregation in the gut neurons with advancing age. A progressive gut microbial composition alteration characterized by the reduction of Firmicutes to Bacteroidetes ratio could be detected in the young transgenic rat model and interestingly this ratio was then increased with aging. This observation was accompanied in older animals by intestinal inflammation, increase gut permeability and a robust alteration in metabolites production characteriz...

Annals of Neurology

Objective: Excessive inflammation in the CNS and the periphery can result in neurodegeneration and parkinsonism. Recent evidence suggests that immune responses in Parkinson"s disease patients are dysregulated, leading to an increased inflammatory reaction to unspecific triggers. Although alpha-synuclein pathology is the hallmark of Parkinson"s disease, it has not been investigated if pathologic alpha-synuclein is a specific trigger for excessive inflammatory responses in Parkinson"s disease. Methods: We investigated the immune response of primary human monocytes and a microglial cell line to pathologic forms of alpha-synuclein by assessing cytokine release upon exposure. Results: We show that pathologic alpha-synuclein (mutations, aggregation) results in a robust inflammatory activation of human monocytes and microglial BV2 cells. The activation is conformation-dependent, with increasing fibrillation and early-onset mutations having the strongest effect on immune activation. We also found that activation of immune cells by extracellular alpha-synuclein is potentiated by extracellular vesicles, possibly by facilitating the uptake of alpha-synuclein. Blood extracellular vesicles from Parkinson"s disease patients induce a stronger activation of monocytes than blood extracellular vesicles from healthy controls. Most importantly, monocytes from Parkinson"s disease patients are dysregulated and hyperactive in response to stimulation with pathologic alpha-synuclein. Furthermore, we demonstrate that α-syn pathology in the CNS is sufficient to induce the monocyte dysregulation in the periphery of a mouse model. Interpretation: Taken together, our data suggests that alpha-synuclein pathology and dysregulation of monocytes in Parkinson"s disease can act together to induce excessive inflammatory responses to alpha-synuclein.

The aggregation of alpha synuclein (a-syn) is a neuropatho-logical feature that defines a spectrum of disorders collectively termed synucleinopathies, and of these, Parkinson's disease (PD) is arguably the best characterized. Aggregated a-syn is the primary component of Lewy bodies, the defining pathological feature of PD, while mutations or multiplications in the a-syn gene result in familial PD. The high correlation between a-syn burden and PD has led to the hypothesis that a-syn aggregation produces toxicity through a gain-of-function mechanism. However, a-syn has been implicated to function in a diverse range of essential cellular processes such as the regulation of neurotransmission and response to cellular stress. As such, an alternative hypothesis with equal explanatory power is that the aggregation of a-syn results in toxicity because of a toxic loss of necessary a-syn function, following sequestration of functional forms a-syn into insoluble protein aggregates. Within this review, we will provide an overview of the literature linking a-syn to PD and the knowledge gained from current a-syn-based animal models of PD. We will then interpret these data from the viewpoint of the a-syn loss-of-function hypothesis and provide a potential mechanistic model by which loss of a-syn function could result in at least some of the neurodegeneration observed in PD. By providing an alternative perspective on the etiopathogenesis of PD and synucleinopathies, this may reveal alternative avenues of research in order to identify potential novel therapeutic targets for disease modifying strategies.

Journal of Neural Transmission, 2019

Parkinson's disease (PD) comprises a spectrum of disorders with differing subtypes, the vast majority of which share Lewy bodies (LB) as a characteristic pathological hallmark. The process(es) underlying LB generation and its causal trigger molecules are not yet fully understood. α-Synuclein (α-syn) is a major component of LB and SNCA gene missense mutations or duplications/triplications are causal for rare hereditary forms of PD. As typical sporadic PD is associated with LB pathology, a factor of major importance is the study of the α-syn protein and its pathology. α-Syn pathology is, however, also evident in multiple system atrophy (MSA) and Lewy body disease (LBD), making it non-specific for PD. In addition, there is an overlap of these α-synucleinopathies with other protein-misfolding diseases. It has been proven that α-syn, phosphorylated tau protein (pτ), amyloid beta (Aβ) and other proteins show synergistic effects in the underlying pathogenic mechanisms. Multiple cell death mechanisms can induce pathological protein-cascades, but this can also be a reverse process. This holds true for the early phases of the disease process and especially for the progression of PD. In conclusion, while rare SNCA gene mutations are causal for a minority of familial PD patients, in sporadic PD (where common SNCA polymorphisms are the most consistent genetic risk factor across populations worldwide, accounting for 95% of PD patients) α-syn pathology is an important feature. Conversely, with regard to the etiopathogenesis of α-synucleinopathies PD, MSA and LBD, α-syn is rather a bystander contributing to multiple neurodegenerative processes, which overlap in their composition and individual strength. Therapeutic developments aiming to impact on α-syn pathology should take this fact into consideration.

Neurobiology of disease, 2017

Parkinson's disease (PD) is a complex, chronic and progressive neurodegenerative disease. While the etiology of PD is likely multifactorial, the protein α-synuclein is a central component to the pathogenesis of the disease. However, the mechanism by which α-synuclein causes toxicity and contributes to neuronal death remains unclear. Mitochondrial dysfunction is also widely considered to play a major role in the underlying mechanisms contributing to neurodegeneration in PD. This review discusses evidence for the neuropathological role for α-synuclein in the dysfunction of dopamine neurons in PD. We also discuss insights into the structure, localization, and cellular roles for α-synuclein that may influence its aggregation properties, ultimately impacting its pathogenicity, role in lysosomal dysfunction and activation of the neuroimmune response. We further highlight recent evidence linking α-synuclein and mitochondrial dysfunction in neurodegeneration. Identifying the underlying ...

Neural plasticity, 2017

Synaptopathies are diseases with synapse defects as shared pathogenic features, encompassing neurodegenerative disorders such as Parkinson's disease (PD). In sporadic PD, the most common age-related neurodegenerative movement disorder, nigrostriatal dopaminergic deficits are responsible for the onset of motor symptoms that have been related to α-synuclein deposition at synaptic sites. Indeed, α-synuclein accumulation can impair synaptic dopamine release and induces the death of nigrostriatal neurons. While in physiological conditions the protein can interact with and modulate synaptic vesicle proteins and membranes, numerous experimental evidences have confirmed that its pathological aggregation can compromise correct neuronal functioning. In addition, recent findings indicate that α-synuclein pathology spreads into the brain and can affect the peripheral autonomic and somatic nervous system. Indeed, monomeric, oligomeric, and fibrillary α-synuclein can move from cell to cell an...

Biological Chemistry, 2017

Alpha-synuclein (α-syn) is an abundant neuronal protein whose physiological function, even if still not completely understood, has been consistently related to synaptic function and vesicle trafficking. A group of disorders known as synucleinopathies, among which Parkinson’s disease (PD), is deeply associated with the misfolding and aggregation of α-syn, which can give rise to proteinaceous inclusion known as Lewy bodies (LB). Proteostasis stress is a relevant aspect in these diseases and, currently, the presence of oligomeric α-syn species rather than insoluble aggregated forms, appeared to be associated with cytotoxicity. Many observations suggest that α-syn is responsible for neurodegeneration by interfering with multiple signaling pathways. α-syn protein can directly form plasma membrane channels or modify with their activity, thus altering membrane permeability to ions, abnormally associate with mitochondria and cause mitochondrial dysfunction (i.e. mitochondrial depolarization...

Molecular Neurobiology, 2013

Parkinson's disease patients exhibit progressive spreading of aggregated α-synuclein in the nervous system. This slow process follows a specific pattern in an inflamed tissue environment. Recent research suggests that prion-like mechanisms contribute to the propagation of α-synuclein pathology. Little is known about factors that might affect the prion-like behavior of misfolded α-synuclein. In this review, we suggest that neuroinflammation plays an important role. We discuss causes of inflammation in the olfactory bulb and gastrointestinal tract and how this may promote the initial misfolding and aggregation of α-synuclein, which might set in motion events that lead to Parkinson's disease neuropathology. We propose that neuroinflammation promotes the prion-like behavior of α-synuclein and that novel antiinflammatory therapies targeting this mechanism could slow disease progression.

Movement Disorders, 2010

Alpha-synuclein (a-syn) appears to normally regulate neurotransmitter release, possibly via calcium-dependent binding and dissociation from lipid domains on secretory vesicles. The pathogenic effects of a-syn leading to Parkinson's disease (PD) appear to result from alternate toxic effects on lipid membrane. A variety of findings indicate that overexpression of wild-type a-syn, pathogenic mutations of a-syn, and dopamine-modified-a-syn promote toxic interaction between a-syn oligomers and lipids. These may disrupt transmembrane concentration gradients across secretory vesicles and other organelles and interfere with normal lysosomal or ubiqutin/proteasome mediated protein degradation or mitochondrial function. Additional causes of PD may interfere at other points with normal handling and degradation of a-syn, providing a variety of entry points to a converging neurodegenerative path underlying the disease.