Journal of Neuroinfectious Diseases
Open Access

Alpha-synuclein is a small, intrinsically disordered protein predominantly found in neural tissue, particularly in presynaptic terminals. It plays a crucial role in synaptic function, neurotransmitter release, and neuroplasticity. However, its aggregation is a hallmark of several neurodegenerative disorders, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Understanding alpha-synuclein's normal function, misfolding, and aggregation mechanisms is essential for developing therapeutic strategies against these debilitating diseases. Structurally, alpha-synuclein is a 140-amino acid protein encoded by the SNCA gene located on chromosome 4q22. It consists of three primary domains: The N-terminal domain, which facilitates membrane binding; the non-amyloid beta-component (NAC) domain, which is prone to aggregation; and the C-terminal domain, which interacts with proteins and metal ions. Under physiological conditions, alpha-synuclein exists as a monomer or helical tetramer, predominantly in the cytoplasm and synaptic vesicles. It is believed to regulate synaptic vesicle trafficking, neurotransmitter release, and neuronal plasticity. However, in pathological conditions, alpha-synuclein undergoes misfolding and aggregation, leading to the formation of toxic oligomers and fibrils. The accumulation of misfolded alpha-synuclein in neuronal and glial cells is a defining characteristic of synucleinopathies. This aggregation disrupts cellular processes, leading to neurodegeneration and progressive functional impairment [1,2]. Understanding the underlying mechanisms of alpha-synuclein pathology is crucial for developing targeted interventions. Ongoing research focuses on reducing alpha-synuclein levels, preventing aggregation, enhancing clearance, and mitigating downstream neurotoxic effects. As therapeutic advancements continue, the hope is to develop effective treatments that can halt or reverse the progression of alpha-synuclein-related disorders [3,4].

Discussion

The role of alpha-synuclein in neurodegenerative diseases has been extensively studied, yet its exact physiological function and the mechanisms underlying its pathological aggregation remain incompletely understood. One of the primary factors contributing to its neurotoxicity is its ability to form toxic oligomers and fibrils. These aggregates interfere with cellular homeostasis by impairing synaptic transmission, mitochondrial function, and protein degradation pathways [5].

A key challenge in understanding alpha-synuclein pathology is its ability to spread between neurons in a prion-like manner. Misfolded alpha-synuclein can propagate through interconnected neural circuits, leading to the progressive spread of pathology observed in synucleinopathies. This property has significant implications for disease progression and treatment strategies aimed at halting its spread [6].

Genetic mutations in the SNCA gene, as well as duplications and triplications of the gene, are linked to familial forms of PD. These genetic alterations increase the expression of alpha-synuclein, promoting its aggregation and accelerating disease onset. Environmental factors, such as oxidative stress, inflammation, and exposure to neurotoxins, also contribute to the misfolding and accumulation of alpha-synuclein in sporadic cases [7].

Therapeutic strategies targeting alpha-synuclein aggregation are being actively explored. Immunotherapies using monoclonal antibodies aim to clear extracellular alpha-synuclein and prevent its cell-to-cell transmission. Small molecule inhibitors are also under development to block fibril formation and enhance protein clearance via autophagy and proteasomal pathways. Additionally, gene silencing approaches seek to reduce the overall expression of alpha-synuclein, thereby decreasing its pathological burden [8].

Despite these promising approaches, challenges remain in translating these strategies into effective clinical treatments. Further research is needed to refine these therapies and develop biomarkers for early diagnosis and monitoring disease progression. A deeper understanding of alpha-synuclein’s physiological and pathological roles will be crucial in advancing therapeutic interventions for neurodegenerative disorders [9].

Structure and Function of Alpha-Synuclein

Alpha-synuclein is a 140-amino acid protein encoded by the SNCA gene located on chromosome 4q22. Structurally, it consists of three domains:

N-terminal domain (residues 1-60) – This region facilitates membrane binding and interacts with phospholipids.

Non-amyloid beta-component (NAC) domain (residues 61-95) – This segment is prone to aggregation and is crucial for fibril formation.

C-terminal domain (residues 96-140) – This domain is highly disordered and interacts with proteins, chaperones, and metal ions.

Under physiological conditions, alpha-synuclein exists as a monomer or helical tetramer, predominantly in the cytoplasm and synaptic vesicles. It is believed to regulate synaptic vesicle trafficking, neurotransmitter release, and neuronal plasticity. However, in pathological conditions, alpha-synuclein undergoes misfolding and aggregation, leading to the formation of toxic oligomers and fibrils [10].

Alpha-Synuclein Aggregation and Pathology

The aggregation of alpha-synuclein is a defining characteristic of synucleinopathies, particularly PD. The misfolded protein accumulates into Lewy bodies and Lewy neurites, which are intracellular inclusions that disrupt neuronal function and lead to neurodegeneration.

Mechanisms of Aggregation

Several factors contribute to alpha-synuclein aggregation, including:

Post-translational modifications (PTMs) – Phosphorylation, ubiquitination, nitration, and truncation can enhance its propensity to aggregate.

Genetic mutations – Point mutations in SNCA, such as A30P, E46K, and A53T, increase aggregation tendencies and are linked to familial PD.

Oxidative stress and metal interactions – Metals such as iron and copper can promote aggregation through oxidative modifications.

Mitochondrial dysfunction – Impaired mitochondrial function leads to elevated reactive oxygen species (ROS), contributing to protein misfolding.

Dysfunctional protein degradation pathways – The ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathway (ALP) help clear misfolded proteins. Impairment of these pathways results in alpha-synuclein accumulation.

Role in parkinson’s disease

Parkinson’s disease (PD) is the most well-known synucleinopathy, characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta. The accumulation of alpha-synuclein in Lewy bodies is a pathological hallmark of PD. The misfolded protein disrupts cellular homeostasis by interfering with synaptic function, mitochondrial dynamics, and proteostasis mechanisms, leading to neuronal death and motor dysfunction.

Conclusion

Alpha-synuclein plays a pivotal role in maintaining neuronal function but becomes a pathogenic factor when misfolded and aggregated. Its involvement in synucleinopathies, particularly Parkinson’s disease, underscores the importance of developing targeted therapies. Current research focuses on reducing alpha-synuclein levels, preventing aggregation, enhancing its clearance, and mitigating downstream neurotoxic effects. While promising treatments are under investigation, further studies are needed to develop effective disease-modifying therapies for alpha-synuclein-related disorders. The future of alpha-synuclein research lies in a multidisciplinary approach, integrating genetics, molecular biology, and clinical studies to develop effective therapeutics. Understanding the interplay between genetic and environmental factors in alpha-synuclein misfolding will be key to unlocking new avenues for treatment.

1. AA Foroughi et al. (2020) Brain connectivity abnormalities in patients with functional (psychogenic nonepileptic) seizures: a systematic review. Seizure 81:269-275.

Indexed at, Google Scholar, Crossref

2. Sundararajan T, Tesar GE, Jimenez XF (2016) Biomarkers in the diagnosis and study of psychogenic nonepileptic seizures: a systematic review. Seizure 35:11-22.

Indexed at, Google Scholar, Crossref

3. Nath A (2017) Grand challenges in neuroinfectious diseases. Front Neurol 8: 480.

Indexed at, Google Scholar, Crossref

4. Somand D, Meurer W (2009) Central nervous system infections. Emerg Med Clin North Am 27: 89-100.

Indexed at, Google Scholar, Crossref

5. Wilson MR, Sample HA, Zorn KC, Arevalo S, Yu G, et al. (2019) Clinical met genomic sequencing for diagnosis of meningitis and encephalitis. N Engl J Med 380:327-340.

Indexed at, Google Scholar, Crossref

6. Edge L (2008) Neuroinfections: celebrating the past, discussing the present. Lancet Neurol 7: 975.

Indexed at, Google Scholar, Crossref

7. Griffin JW (2006) Neurologists don't do windows. Nat Clin Pract Neurol 2:1.

Google Scholar

8. Epstein LG, Sharer LR, Cho ES, Myenhofer M, Navia B, et al. (1985) HTLV-III/LAV-like retrovirus particles in the brains of patients with AIDS encephalopathy. AIDS Res 1:447-454.

Indexed at, Google Scholar, Crossref

9. Tan K, Patel S, Gandhi N, Chow F, Rumbaugh J, et al. (2008) Burden of neuroinfectious diseases on the neurology service in a tertiary care center. Neurology 71:1160-1166.

Indexed at, Google Scholar, Crossref

10. Johnson TP, Nath A (2018) Neurological syndromes driven by post infectious processes or unrecognized persistent infections. Curr Opin Neurol 31:318-324.

Indexed at, Google Scholar, Crossref