Balancing two forms of SNCA protein could help manage Parkinson’s, study finds

Sub: Science and tech

Sec: Health

Context:

Many Parkinson’s disease researchers are focused on reducing the prevalence of SNCA proteins in neurons as a therapeutic measure.

What is Parkinson’s disease?

Parkinson’s disease is a chronic, degenerative neurological disorder that affects the central nervous system.
It damages nerve cells in the brain, dropping the levels of dopamine.
Dopamine is a chemical that sends behavioral signals from the brain to the body.
The disease causes a variety of “motor” symptoms (symptoms related to movement of the muscles), including rigidity, delayed movement, poor balance, and tremors.
Medication can help control the symptoms of the disease but it can’t be cured.
It affects the age group from 6 to 60 years. Worldwide, about 10 million people have been affected by this disease.
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.

What are SCNA proteins?

Synuclein alpha (SNCA) is a mysterious protein.
Alpha-synuclein (aSyn) is a protein that, in humans, is encoded by the SNCA gene.
Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release.
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 is 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.
It promotes Neuronal Dysfunction and Death by Disrupting the Binding of Ankyrin to beta-Spectrin.
Twenty-seven years ago, researchers first associated SNCA with Parkinson’s disease.
Diseases associated with SNCA include Parkinson Disease 1, Autosomal Dominant and Dementia, Lewy Body.

About the study:

SNCA is present as aggregates in cells in two ways:
- 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.
The study highlights the importance of striking a balance between these two SNCA populations to manage Parkinson’s disease.
Cultivation of neurons: The researchers cultivated neurons outside a living body, providing them with nutrients in a laboratory setup.
Artificially created structure: In these neurons, they artificially created structures resembling Lewy bodies by adding some amount of misfolded SNCA, called seeds.
Two SCNA populations: Over time, two SNCA populations in the cells are witnessed.
- One was around the nuclei, shaped like filaments tens of micrometers 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 localize misfolded proteins into a small bunch (like collecting the trash in a corner) for further processing.
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.

About nucleus of the cell:

A nucleus is the control center of the cell.
It contains the cell’s genetic material, and is the seat of upkeep of this genetic material and its utilization to make proteins.
The accumulation of misfolded SNCA would render the nucleus dysfunctional and eventually kill it.
Lewy-body-like structures can pass from one cell to another, so the effect could cascade to neighboring cells as well.

Various therapeutic impacts:

A smaller population of SNCA means fewer misfolded SNCA.
This can be achieved by stopping the SNCA gene from expressing itself or by destroying the SNCA protein inside cells, once the cells make them.
Another workable solution has been to use a gene-silencing tool, like CRISPR-Cas9, at a precise location.

Terms in news:

Lewy Bodies:

Lewy bodies are clumps of abnormal protein particles that, for reasons that are not fully understood, accumulate in the brain.
These deposits cause a form of dementia called Lewy body dementia, or LBD — which is what the late actor and comedian Robin Williams suffered from.

CRISPR:

CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats.
CRISPR-Cas9 is the most prominent technology that enables editing parts of the genome by removing, adding or altering sections of the DNA sequence.
The CRISPR-Cas9 system consists of two key molecules that introduce a change mutation into the DNA.
Cas9- An enzyme that acts as a pair of ‘molecular scissors’ that can cut the two strands of DNA at a specific location in the genome.
Guide RNA (gRNA)- The gRNA is designed to find and bind to a specific sequence in the DNA.