News Excerpt:
Parkinson’s is treated symptomatically by increasing the levels of dopamine or, more drastically, by grafting new neurons in place of dead ones. A solution based on the SNCA protein is more desirable because it will offer a more sustainable resolution.
About Synuclein alpha (SNCA):
- SNCA is a mysterious protein present in healthy cells, but its normal function is not well understood. It is notorious for its involvement in age-related neurodegenerative diseases, particularly Parkinson's disease.
- In Parkinson's disease, dopaminergic neurons (neurons that communicate using dopamine) in the brain are lost, and these neurons contain aggregated masses of proteins called Lewy bodies, primarily composed of SNCA.
- SNCA is abundant in neurons, especially dopaminergic neurons, and is found near the nuclei of these cells and at the junctions between neurons.
- SNCA is capable of misfolding and forming filamentous structures, which is unusual compared to most other proteins with predictable three-dimensional structures.
Two populations
- A recent study from researchers lab at the CSIR-Centre for Cellular and Molecular Biology, Hyderabad, published in the Journal of Cell Science, reported two ways in which SNCA is present as aggregates in cells:
- one that interferes with the structural integrity of cells' nuclei
- Another that allows the cell to degrade misfolded proteins.
Breaching the nucleus
- They noticed that the Lewy-body-like structures formed very slowly. Most of the time, the aggresomes took up the SNCA proteins and didn't allow the Lewy-body-like structures to grow.
- But in their experiment, when the researchers repeatedly seeded neurons with misfolded SNCA, the Lewy-body-like structures formed faster and became big enough to affect other parts of the cell.
- The enlarged Lewy-body-like structures were situated at the periphery of the nuclei of the cells, and the researchers have argued that this damages the nuclear envelope. Sometimes, the structures also enter the ruptured nucleus.
A therapeutic Measures
Many Parkinson’s disease researchers are focused on reducing the prevalence of SNCA in neurons as a therapeutic measure.
- Reducing SNCA Content: A smaller population of SNCA means fewer misfolded SNCA, too. Researchers have achieved this by stopping the SNCA gene from expressing itself or by destroying the SNCA protein inside cells, once the cells make them.
- Using Gene-Silencing Tools: Another workable solution has been to use a gene-silencing tool, like CRISPR-Cas9, at a precise location.
- Researchers have tried this method in cell cultures and model animals.
- But a significant challenge is to cross the blood-brain barrier, a liquid that filters the blood that goes into the brain, and which would also prevent a component CRISPR from passing through
- Overcoming Blood-Brain Barrier: some researchers have tried to inject molecules that inhibit the SNCA gene through the skull, directly into the desired brain region. Others have used small molecules like modified viruses to beat the barrier.
- Some researchers have also identified enzymes that degrade proteins in select brain cells, but with varying efficacy.
- Preventing SNCA Aggregation: Researcher has suggested balancing the SNCA population between aggresomes and Lewy bodies. The more SNCA that goes into the aggresomes, the less there will be available to make Lewy bodies. How this can be achieved is still being worked out.
Potential Impact:
- Even if any one of these methods succeeds, it will transform the way Parkinson’s disease is treated today.
- Parkinson’s is treated symptomatically by increasing the levels of dopamine or, more drastically, by grafting new neurons in place of dead ones.
- An SNCA-based solution is more desirable because it offers a more sustainable resolution.
