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Target: SNCA


Research on the Target SNCA

1. Target Summary:

SNCA (Synuclein Alpha) is a gene that encodes the protein alpha-synuclein, which is primarily expressed in the brain and is involved in synaptic function. It is a key player in the pathogenesis of neurodegenerative diseases, particularly Parkinson's disease (PD) and other synucleinopathies such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Mutations and polymorphisms in the SNCA gene are associated with familial forms of PD, and the accumulation of misfolded alpha-synuclein is a hallmark of these diseases.

2. Mechanism:

Alpha-synuclein is involved in synaptic vesicle regulation and neurotransmitter release. In healthy neurons, it exists in a soluble form, but under pathological conditions, it misfolds and aggregates into oligomers and fibrils, forming Lewy bodies. This aggregation disrupts neuronal function and leads to cell death through several mechanisms:
  • Neuroinflammation: Aggregated alpha-synuclein activates microglia, leading to an inflammatory response that exacerbates neuronal damage (Liu et al., 2022, PMID: 35456966).
  • Mitochondrial Dysfunction: Alpha-synuclein aggregates impair mitochondrial function, leading to increased oxidative stress and neuronal apoptosis (Picca et al., 2021, PMID: 34680141).
  • Impaired Protein Clearance: The accumulation of alpha-synuclein disrupts the ubiquitin-proteasome and autophagy-lysosomal systems, further contributing to neurodegeneration (Hatano et al., 2024, PMID: 38589016).

3. Approved Drugs:

Currently, there are no drugs specifically approved to target SNCA or alpha-synuclein aggregation. However, several therapeutic strategies are under investigation, including:
  • Immunotherapy: Approaches aimed at reducing alpha-synuclein levels or preventing its aggregation.
  • Gene Therapy: Strategies to modify the expression of SNCA or enhance its clearance from neurons.

4. Hypotheses:

  • Aggregation Hypothesis: Mutations in SNCA lead to increased aggregation of alpha-synuclein, which is toxic to neurons and contributes to the development of PD (Mehra et al., 2019, PMID: 30853581).
  • Environmental Interaction Hypothesis: Environmental factors, such as exposure to pesticides, may interact with genetic predispositions related to SNCA, increasing the risk of developing PD (Pang et al., 2019, PMID: 31428316).
  • Biomarker Hypothesis: Alpha-synuclein levels in biological fluids (e.g., cerebrospinal fluid, serum) can serve as biomarkers for early diagnosis and disease progression in PD (Yan et al., 2024, PMID: 38048087).

5. Validation:

The role of SNCA in PD has been validated through various studies:
  • Genetic studies have identified pathogenic variants in SNCA associated with familial PD (Lim & Klein, 2024, PMID: 38589016).
  • Biomarker studies have demonstrated that elevated levels of aggregated alpha-synuclein correlate with disease severity and progression (Simuni et al., 2024, PMID: 38267190).
  • Clinical trials targeting alpha-synuclein aggregation are ongoing, providing further validation of its role as a therapeutic target (Polissidis et al., 2020, PMID: 32560161).

6. Clinical Trials:

Several clinical trials are currently investigating therapies targeting SNCA:
  • Immunotherapy Trials: These trials aim to evaluate the efficacy of antibodies against alpha-synuclein in reducing its aggregation and improving clinical outcomes in PD patients.
  • Gene Therapy Trials: Investigating the potential of gene editing technologies to modify SNCA expression or enhance its clearance from neurons.

7. Involved Pathways:

  • Ubiquitin-Proteasome Pathway: Impaired function of this pathway leads to the accumulation of misfolded proteins, including alpha-synuclein.
  • Autophagy-Lysosomal Pathway: Dysfunction in autophagy contributes to the accumulation of alpha-synuclein aggregates.
  • Neuroinflammatory Pathways: Activation of microglia and the release of pro-inflammatory cytokines exacerbate neuronal damage.

8. Associated Genes:

  • SNCA: Encodes alpha-synuclein.
  • LRRK2: Another gene associated with familial PD.
  • GBA: Mutations in this gene are a significant risk factor for PD and interact with alpha-synuclein pathology.

9. Target Expression:

SNCA is predominantly expressed in the brain, particularly in the presynaptic terminals of neurons. Its expression levels can be influenced by genetic variants and environmental factors, which may affect the risk of developing PD.

10. Additional Context:

The understanding of SNCA's role in PD has evolved significantly, with ongoing research focusing on its potential as a biomarker for early diagnosis and as a target for disease-modifying therapies. The interplay between genetic predispositions and environmental factors continues to be a critical area of investigation.

11. References:

  • Liu TW, Chen CM, Chang KH. Biomarker of Neuroinflammation in Parkinson's Disease. International journal of molecular sciences. 2022 Apr 8. PMID: 35456966.
  • Hatano T, Okuzumi A, Matsumoto G. alpha-Synuclein: A Promising Biomarker for Parkinson's Disease and Related Disorders. Journal of movement disorders. 2024 Apr. PMID: 38589016.
  • Simuni T, Chahine LM, Poston K. A biological definition of neuronal alpha-synuclein disease: towards an integrated staging system for research. The Lancet. Neurology. 2024 Feb. PMID: 38267190.
  • Pang SY, Ho PW, Liu HF. The interplay of aging, genetics and environmental factors in the pathogenesis of Parkinson's disease. Translational neurodegeneration. 2019. PMID: 31428316.
  • Polissidis A, Petropoulou-Vathi L, Nakos-Bimpos M. The Future of Targeted Gene-Based Treatment Strategies and Biomarkers in Parkinson's Disease. Biomolecules. 2020 Jun 16. PMID: 32560161.
  • Yan S, Jiang C, Janzen A. Neuronally Derived Extracellular Vesicle alpha-Synuclein as a Serum Biomarker for Individuals at Risk of Developing Parkinson Disease. JAMA neurology. 2024 Jan 1. PMID: 38048087.