Synuclein alpha (SNCA) is a mysterious protein. It’s present in healthy cells but we don’t know what it does there. It is notorious for its involvement in age-related neurodegenerative diseases. Twenty-seven years ago, researchers first associated SNCA with Parkinson’s disease. People with this disease lose neurons that communicate with each other using dopamine as a neurotransmitter in a part of their brains.
These dopaminergic neurons have been found to contain aggregated masses of proteins called Lewy bodies. Most of these proteins are SNCA.
Since then, researchers have reported SNCA in similar aggregates in the brains of people with other neurodegenerative diseases as well. But its presence is most prominent in brains with Parkinson’s.
SNCA is abundant in neurons, especially in dopaminergic neurons. It is found near the nuclei of these cells and at the junctions between two neurons. It’s capable of misfolding as well as forming filamentous structures. So unlike most other proteins, which take up predictable three-dimensional structures, SNCA can fold in multiple ways. Misfolded proteins don’t function correctly.
But beyond these observations, researchers don’t understand the dynamics of the formation of these aggregates and how exactly they affect neurons.
Two populations
A recent study from Swasti Raychaudhuri’s 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 and another that allows the cell to degrade misfolded proteins. The researchers found that the former are related to diseased states while the latter is important for healthy cells.
As such, the study highlights the importance of striking a balance between these two SNCA populations to manage Parkinson’s disease.
The researchers cultivated neurons outside a living body, providing them with nutrients in a laboratory setup. In these neurons, they artificially created structures resembling Lewy bodies by adding some amount of misfolded SNCA, called seeds.
Over time, they found two SNCA populations in the cells: one was around the nuclei, shaped like filaments tens of micrometres long, much like Lewy bodies. The other population was also around the nuclei but as much smaller clumps called aggresomes. Such aggresomes are formed when cells localise misfolded proteins into a small bunch (like collecting the trash in a corner) for further processing.
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. At one point, they became too populous for the aggresomes to mitigate their prevalence.
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 entered the ruptured nucleus.
A nucleus is the control centre of the cell. It contains the cell’s genetic material, and is the seat of upkeep of this genetic material and its utilisation to make proteins. So it is logical that the accumulation of misfolded SNCA would render the nucleus dysfunctional and eventually kill it. In addition, Lewy-body-like structures can pass from one cell to another, so the effect could cascade to neighbouring cells as well.
Dr. Raychaudhuri’s team was able to cross-check its findings in mice with Lewy-body-like structures in their brains. They reported that the increasing prevalence of these structures induced conditions mimicking Parkinson’s disease. They also found that all the cells so affected also had damaged nuclear envelopes.
A therapeutic target?
Many Parkinson’s disease researchers are focused on reducing the prevalence of SNCA in neurons as a therapeutic measure. Researchers are going about this in various ways, but haven’t yet found one that has been approved for sale.
One way is to reduce the cells’ 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. However, either of these interventions needs to happen only in select locations: if all the SNCA everywhere is taken away, the animal body will die.
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.
To surmount this 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.
Another possibility is to stop SNCA from forming large aggregates. Dr. Raychaudhuri 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.
Even if any one of these methods succeeds, it will transform the way Parkinson’s disease is treated today. 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.
Somdatta Karak, PhD heads science communication and public outreach at CSIR-Centre for Cellular and Molecular Biology.
