Editorial 1 : Balancing two forms of SNCA protein could help manage Parkinson’s
Context
Today, 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
SNCA protein
- 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 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.
A therapeutic target?
- Many Parkinson’s disease researchers are focused on reducing the prevalence of SNCA in neurons as a therapeutic measure.
- 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.
- Another possibility is to stop SNCA from forming large aggregates. They have 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.
Conclusion
Even if any one of these methods succeeds, it will transform the way Parkinson’s disease is treated today.
Editorial 2 : Renew the generalised system of preferences
Context
It is clear there needs to be higher ambition on trade in order to take the U.S.-India strategic relationship even further
The GSP
- In the pantheon of obscure international trade terminology, the “generalised system of preferences,” or GSP, has a special place.
- GSP refers to an approach that has been adopted by nearly all developed countries for roughly the last half-century to offer incentives for economic reform in developing countries through lower tariffs.
- Each developed country has customised its own GSP programme to identify qualification criteria it deems important in economic reform, although all ensure that their programmes are constructed to avoid harm to domestic production.
- In short, it is the oldest and most far-reaching approach to “aid for trade” in the modern multilateral trading system, embodied in the World Trade Organization.
Renewing GSP and it’s importance
- New legislation is never an easy proposition, especially in a polarised environment, making bipartisan legislation a herculean endeavour.
- GSP can play a vital role in establishing stable market access for developing countries that otherwise struggle to tap into global trade flows.
- It can be especially valuable for small businesses and women-owned enterprises, thus helping to empower them beyond limited domestic markets.
- More recent analysis suggests that GSP is vital in offering alternatives to Chinese imports and providing an advantage to suppliers in trusted developing country markets.
- GSP criteria promote reforms on labour and environmental sustainability and intellectual property rights protection.
- GSP imports also help reduce the tariff bills paid by American companies, many of which are small- and medium-sized enterprises.
- n an era of friendshoring and nearshoring, GSP can be an effective tool in pursuing new supply chain objectives. Surprisingly, there is even strong bipartisan support for restarting GSP talks with India.
U.S.-India trade relationship
- It is accepted wisdom that GSP renewal would offer an avenue for wide-ranging U.S.-India trade negotiations that can help in vaulting the bilateral trade relationship from the $200 billion it is presently at to a much higher level.
- It is clear there needs to be higher ambition on trade in order to take the U.S.-India strategic relationship even further.
- Before the expiration of the GSP programme in 2020, negotiations between the Office of the U.S. Trade Representative and the Indian Ministry of Commerce and Industry had come close to sealing a wide-ranging deal.
- Estimates at the time suggested that an unprecedented bilateral trade agreement between the U.S. and India might cover as much as $10 billion in trade, including medical devices, several agricultural commodities, corn-based ethanol used for fuel, and information technology products.
- Even though India has gone into overdrive in negotiating free trade agreements (FTAs) with a wider circle of trading partners, including the European Union, the U.K., the European Free Trade Association, Australia, and the UAE, the Biden administration is clear that the U.S. will not negotiate FTAs with any country for the moment.
- There are several trade dialogues between the two, but these lack the leverage for a hard-nosed trade negotiation that can shoot for ambitious results.
- The private sectors in both countries are teaming up to increase investments in high-profile sectors across critical and emerging technologies from smartphone manufacturing to semiconductor production, but they lack the stability in regulatory certainty and ease of doing business that a strong, enforceable trade agreement can bring.
Conclusion
As the U.S.-India strategic partnership continues to grow and the two countries play critical, collaborative roles in the Indo-Pacific, they should aim much higher in their trade relationship. GSP is not the full answer to comprehensively achieving this, but it would be a strong statement of their mutual desire to be on this path.