SNCA PROTEINS AND PARKINSON’S DISEASE

Source: Hindu

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Context

• Parkinson's disease, a debilitating neurodegenerative disorder, is currently managed through symptomatic treatments that either boost dopamine levels or involve neuron grafting.
• However, a potential solution focusing on the SNCA (synuclein alpha) protein could offer a more sustainable treatment method.

Details

Understanding SNCA

• Presence in Neurons:
  • SNCA is prevalent in neurons, particularly dopaminergic neurons, which are critical for dopamine neurotransmission.
  • It exists near the cell nuclei and at neuronal junctions, capable of misfolding and forming filamentous structures.
• Role in Disease:
  • Misfolded SNCA forms Lewy bodies, contributing to the loss of neuronal function and eventual cell death.
  • Its aggregates are also found in other neurodegenerative diseases, though most notably in Parkinson’s.

Recent Research Findings

• A recent study by Swasti Raychaudhuri’s lab at the CSIR-Centre for Cellular and Molecular Biology in Hyderabad sheds light on the dual nature of SNCA aggregates in cells:

1.Two SNCA Populations:

• Lewy Body-Like Structures: Filamentous aggregates around the nucleus that disrupt cellular integrity.
• Aggresomes: Smaller clumps that localize misfolded proteins for degradation, promoting cellular health.

2.Balance and Disease:

• Healthy cells manage misfolded proteins via aggresomes, preventing the formation of harmful Lewy bodies.
• Excessive misfolded SNCA overwhelms the cell’s capacity, leading to Lewy body formation and subsequent cellular damage.

Therapeutic Implications

Current Parkinson's treatments focus on symptomatic relief, but managing SNCA levels offers a promising alternative:

• Reducing SNCA Content: Strategies include inhibiting SNCA gene expression or degrading SNCA protein, requiring targeted interventions to avoid systemic effects.
• Gene-Silencing Tools: Techniques like CRISPR-Cas9 have been explored in cell cultures and animal models, though challenges like crossing the blood-brain barrier remain.
• Preventing Aggregate Formation: Dr. Raychaudhuri suggests increasing SNCA sequestration into aggresomes to reduce Lewy body formation, though precise methods need further development.

About SNCA Protein

Basic Characteristics:

• Protein Family:Synuclein family, which also includes beta-synuclein and gamma-synuclein.
• Amino Acids:Composed of 140 amino acids.
• Molecular Weight:Approximately 14 kDa.
• Structure:
  • Lacks a stable three-dimensional structure in solution, classified as an intrinsically disordered protein (IDP).
  • Can adopt alpha-helical or beta-sheet conformations under different conditions.
• Localization:
• Cellular Distribution:Found in the cytoplasm, nucleus, and particularly at presynaptic terminals of neurons.
• Tissue Specificity:Abundant in the brain, especially in dopaminergic neurons.

Functions:

• Synaptic Vesicle Regulation:Involved in the regulation of neurotransmitter release.
• Membrane Interaction:Binds to lipid membranes, potentially involved in membrane trafficking.
• Mitochondrial Function:May play a role in maintaining mitochondrial function and integrity.
• Protein Aggregation:Misfolding of SNCA leads to the formation of aggregates known as Lewy bodies.
• Neurotoxicity:Aggregated SNCA is toxic to neurons, disrupting cellular processes and leading to cell death.

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Sources:

Hindu

PRACTICE QUESTION Q. The SNCA protein is central to our understanding of Parkinson’s disease and other neurodegenerative disorders. Comment. (150 Words)