A functional role for alpha-synuclein in neuroimmune responses

Heiden, Dustin L.; Monogue, Brendan; Ali, Muhammad; Beckham, J. David

doi:10.1016/j.jneuroim.2023.578047

Cited by 8 publications

(3 citation statements)

References 131 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While specific neuronal populations (dopamine neurons in the substantia nigra) are affected in PD, there is also a considerable overlap between AD and ALS in pathogenic mechanisms [27][28][29][30]. In keeping with this, complex interactions have been revealed between α-syn, a neuronal protein associated with PD and other synucleinopathies, and microglia [141]. Like in ALS and AD, microglia are neuroprotective in the early stages of disease by clearing α-syn, whereas during the chronic disease stage, they are considered to promote neurodegeneration by propagating the α-syn burden and creating an inflammatory environment [142].…”

Section: Immune Imbalance In Parkinson's Diseasementioning

confidence: 96%

Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders

De Marchi,

Munitic,

Vidatic

et al. 2023

Biomedicines

View full text Add to dashboard Cite

Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer’s (AD) disease, Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), as well as in a seemingly distinct Niemann–Pick type C disease with primarily juvenile onset. This strongly argues for an overlap in pathogenic mechanisms. The commonly researched immune targets include various immune cell subsets, such as microglia, peripheral macrophages, and regulatory T cells (Tregs); the complement system; and other soluble factors. In this review, we compare these neurodegenerative diseases from a clinical point of view and highlight common pathways and mechanisms of protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies for overlapping immune dysfunctions in these diseases. These approaches include but are not limited to immunisation, complement cascade blockade, microbiome regulation, inhibition of signal transduction, Treg boosting, and stem cell transplantation.

show abstract

Section: Immune Imbalance In Parkinson's Diseasementioning

confidence: 96%

Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders

De Marchi,

Munitic,

Vidatic

et al. 2023

Biomedicines

View full text Add to dashboard Cite

show abstract

“…Intriguingly, they present a deficient immune defense against infectious agents [25,26]. These observations are connected to the recent demonstration that ␣-synuclein is essential for the development of a normal inflammatory response to the intraperitoneal injection of bacterial peptidoglycan and for antigen-specific and T cell responses, which led to recent advocations that the main physiological function of this protein would be more related to the immune function than neuronal activity regulation [27,28]. In fact, several studies demonstrating an important interplay with immune response reinforce this hypothesis.…”

Section: Synucleinopathies and ␣-Synucleinmentioning

confidence: 98%

RAGE Against the Glycation Machine in Synucleinopathies: Time to Explore New Questions

Gelain

Bittencourt

Mendes

et al. 2023

Journal of Parkinson’s Disease

View full text Add to dashboard Cite

Oligomerization and aggregation of misfolded forms of α-synuclein are believed to be key molecular mechanisms in Parkinson’s disease (PD) and other synucleinopathies, so extensive research has attempted to understand these processes. Among diverse post-translational modifications that impact α-synuclein aggregation, glycation may take place at several lysine sites and modify α-synuclein oligomerization, toxicity, and clearance. The receptor for advanced glycation end products (RAGE) is considered a key regulator of chronic neuroinflammation through microglial activation in response to advanced glycation end-products, such as carboxy-ethyl-lysine, or carboxy-methyl-lysine. The presence of RAGE in the midbrain of PD patients has been reported in the last decades and this receptor was proposed to have a role in sustaining PD neuroinflammation. However, different PD animal models demonstrated that RAGE is preferentially expressed in neurons and astrocytes, while recent evidence demonstrated that fibrillar, non-glycated α-synuclein binds to RAGE. Here, we summarize the available data on α-synuclein glycation and RAGE in the context of PD, and discuss about the questions yet to be answered that may increase our understanding of the molecular bases of PD and synucleinopathies.

show abstract

“…Moreover, the function of native or monomeric α-syn is not studied in as much detail as that of mutants. Contrary to PD, α-syn plays a neuroprotective role and is also important in pathogen-activated immune responses and lymphocyte maturation (27). In microglia cells, native α-syn leads to an increase in Th1 and Th2 cytokine expressions (28).…”

Section: Introductionmentioning

confidence: 99%

Alpha-synuclein expression in neuron modulates the Japanese encephalitis virus infection

Gupta,

Mohapatra,

Kaur

et al. 2023

Preprint

View full text Add to dashboard Cite

Japanese encephalitis virus (JEV) stands as a prominent vector-borne zoonotic pathogen, displaying neurotropism and eliciting Parkinson’s disease (PD)-like symptoms among most symptomatic survivors. A characteristic feature of PD is aggregation of mutated α-synuclein (α-syn) that damages the dopaminergic neurons. Considering this link between JEV-induced PD-like symptoms and α-syn pathogenesis, we explored the role of α-syn in JEV infectivity in neuronal cells. Our investigation revealed significant increase in endogenous α-syn expression in JEV-infected cells. Additionally, treatment with exogenous α-syn (Exoα-syn) led to a substantial reduction in JEV replication, suggesting its anti-JEV effect. Furthermore, Exoα-syn treatment led to the upregulation of superoxide dismutase 1 (SOD1) and reduction in reactive oxygen species (ROS). The results were validated by endogenous α-syn-silencing, that decreased SOD1 level and raised ROS level in neuronal cells. Similarly, the SOD1 inhibition via LCS-1 also intensified ROS and JEV infection. Overall, our results suggest that α-syn exerts an anti-JEV effect by regulating protein involved in oxidative stress inside neuronal cells. This study contributes valuable insights into the interplay between α-syn expression and JEV infectivity, shedding light on avenues to further investigate the potential role of α-syn in JEV pathogenesis.ImportanceJapanese encephalitis virus (JEV) poses significant threat particularly to children. Despite extensive research efforts, the development of effective treatments against JEV has been impeded. One of the major setbacks is a lack of comprehensive understanding of neurotropism. The study focuses on alpha synuclein (α-syn), a neuronal protein, and aims to determine its role in JEV pathogenesis. Present study reveals that host cell upregulates α-syn in response of JEV infection. α-syn restrains JEV propagation by modulating superoxide dismutase 1 (SOD1) expression which further blocks JEV-induced ROS generation. Endogenous α-syn silencing led to decrease in SOD1 expression and increased viral titer. α-syn plays crucial role in counteracting oxidative stress through SOD1, which is essential for limiting JEV replication. This study provides broader implications for antiviral strategies and its possible role in neurodegenerative diseases; however, there is still much to explore, particularly regarding its aggregation kinetics in JEV infection.

show abstract

A functional role for alpha-synuclein in neuroimmune responses

Cited by 8 publications

References 131 publications

Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders

Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders

RAGE Against the Glycation Machine in Synucleinopathies: Time to Explore New Questions

Alpha-synuclein expression in neuron modulates the Japanese encephalitis virus infection

Contact Info

Product

Resources

About