The SNCA gene plays an important role in human biology, particularly within the nervous system. It is strongly associated with several neurodegenerative diseases, particularly Parkinson’s disease. Understanding this gene offers insights into the mechanisms of these conditions.
The SNCA Gene’s Normal Function
The SNCA gene, which stands for Synuclein Alpha, is located on chromosome 4 at position 4q22.1. It provides instructions for creating the alpha-synuclein protein. Alpha-synuclein is abundant in the brain, with smaller quantities also present in other tissues like the heart and muscles.
Within the brain, alpha-synuclein is primarily situated at the ends of nerve cells, in presynaptic terminals. These terminals are responsible for releasing chemical messengers, known as neurotransmitters, from synaptic vesicles. This release is fundamental for communication between neurons and overall brain function.
While its full function is still being investigated, alpha-synuclein is thought to help maintain a sufficient supply of synaptic vesicles within presynaptic terminals. It may also regulate the release of dopamine, a neurotransmitter that helps control voluntary and involuntary movements. Additionally, alpha-synuclein might contribute to the movement of microtubules, which are structures that assist cells in maintaining their shape.
When the SNCA Gene Goes Wrong
The SNCA gene can malfunction in several ways. Genetic alterations, such as point mutations or the duplication and triplication of the gene, can lead to abnormal or excessive amounts of alpha-synuclein. These genetic changes disrupt the delicate balance required for proper protein function.
When alpha-synuclein goes awry, it can undergo misfolding, where the protein adopts an incorrect three-dimensional shape. These misfolded proteins clump together, forming insoluble aggregates or fibrils. Lewy bodies are a prominent example of these aggregates, found inside neurons.
These protein aggregates can become toxic to neurons, impairing their function and leading to cell death. Researchers suspect that Lewy bodies may disrupt the regulation of dopamine, potentially causing dopamine to accumulate to toxic levels. They may also interfere with the cell’s machinery responsible for removing unneeded proteins, contributing to neuronal damage.
SNCA’s Role in Neurodegenerative Diseases
Dysfunction of the SNCA gene and its resulting alpha-synuclein pathology are closely linked to several neurodegenerative diseases. Parkinson’s disease (PD) is a prime example, where the presence of abnormal alpha-synuclein aggregates, Lewy bodies, is a defining characteristic. Lewy bodies contribute to the selective death or impairment of dopamine-producing neurons in specific brain regions, leading to the motor symptoms associated with PD.
Lewy body dementia (LBD) is another condition strongly associated with SNCA gene mutations, which lead to the production of abnormally shaped alpha-synuclein protein. In LBD, these misshapen proteins cluster throughout the brain, impairing neuron function and causing cell death. The widespread presence of these clusters progressively affects intellectual, motor, and emotional regulation, contributing to LBD symptoms.
Multiple System Atrophy (MSA) also shares this underlying alpha-synuclein pathology, where variations in the SNCA gene have been found to increase the risk of developing this progressive brain disorder. MSA affects movement, balance, and the autonomic nervous system, which controls involuntary actions like blood pressure regulation. The presence and spread of misfolded alpha-synuclein are central to the progression of these diseases, highlighting the shared pathological mechanism.
Targeting SNCA in Research and Therapy
Understanding SNCA and alpha-synuclein is central to advancing research and developing new therapeutic strategies. Current research efforts aim to prevent the alpha-synuclein protein from misfolding. Scientists are investigating compounds that could stabilize the protein’s correct shape or interfere with the aggregation process.
Another focus involves promoting the clearance of misfolded alpha-synuclein from the brain. This could involve enhancing the cell’s natural waste removal systems or developing methods to directly remove the toxic aggregates. Researchers are also exploring ways to block the spread of misfolded alpha-synuclein from one neuron to another, which is believed to contribute to disease progression. These approaches hold promise for developing treatments that could slow or halt the progression of synucleinopathies.