Parkinson’s disease is a progressive neurodegenerative condition that primarily affects movement. Central to its pathology is a protein named alpha-synuclein, found throughout the nervous system. This protein’s transformation from a helpful component to a driver of cellular damage is a primary focus of Parkinson’s research. This article explores alpha-synuclein’s normal functions and its involvement in the disease.
What is Alpha-Synuclein Protein?
Alpha-synuclein is a small protein abundant in the human brain, with smaller amounts in the heart, muscles, and other tissues. It is highly concentrated at the tips of neurons in structures called presynaptic terminals. These terminals release chemical messengers, known as neurotransmitters, from synaptic vesicles to enable communication between neurons.
Alpha-synuclein’s function involves managing the supply and release of synaptic vesicles. It assists in forming SNARE complexes, which are proteins that help vesicles fuse with the cell membrane to release neurotransmitters. This role helps maintain efficient neuronal communication, which is necessary for cognitive functions and movement.
The protein is normally flexible and unfolded but changes shape when interacting with other molecules, like the lipid membranes of synaptic vesicles. This interaction is part of its function, helping remodel membranes and regulate the flow of neurotransmitters such as dopamine. Dopamine is a neurotransmitter that controls movement, highlighting alpha-synuclein’s importance in healthy brain function.
How Alpha-Synuclein Contributes to Parkinson’s
The link between alpha-synuclein and Parkinson’s begins when the protein changes from its soluble form into an abnormal, insoluble state. This process starts with misfolding, where the protein adopts a “sticky” structure rich in beta-sheets. This altered shape causes it to clump together with other misfolded alpha-synuclein proteins.
These initial clumps, known as oligomers, are small but grow by recruiting more misfolded proteins, forming larger, insoluble structures called fibrils. This process is self-propagating, as a small amount of misfolded alpha-synuclein can trigger a cascade of aggregation. This chain reaction is a defining feature of the disease.
These fibrils are the main component of Lewy bodies, which are protein deposits found inside affected neurons. Lewy bodies and smaller aggregates called Lewy neurites are the pathological hallmarks of Parkinson’s. Misfolded proteins may also spread from one neuron to another, which could explain how the disease progresses through the brain.
Impact of Alpha-Synuclein Changes on Brain Cells
The accumulation of misfolded alpha-synuclein disrupts multiple cellular functions, leading to cell death. These protein aggregates interfere with the cell’s waste disposal systems, such as the ubiquitin-proteasome system and autophagy. When these systems become faulty, toxic proteins build up and stress the cell.
Alpha-synuclein clumps are damaging to mitochondria, the cell’s powerhouses. This dysfunction reduces the cell’s energy supply and increases oxidative stress, which can damage cellular components. The aggregates also disrupt material transport along the neuron’s axon and interfere with neurotransmitter release at the synapse.
This cellular dysfunction is especially detrimental to dopamine-producing neurons in the substantia nigra region of the brain. As these vulnerable neurons are damaged and die, the brain’s dopamine supply diminishes. This loss of dopamine leads to the motor symptoms of Parkinson’s, such as tremors, stiffness, and difficulty with movement.
Genetic Factors Involving Alpha-Synuclein
While most Parkinson’s cases are sporadic, with no clear cause, genetics can play a role. The gene that provides instructions for making alpha-synuclein is SNCA. Certain rare variations in this gene are directly linked to inherited forms of the disease.
One genetic link involves point mutations in the SNCA gene, which are small errors in the genetic code. These mutations result in an alpha-synuclein protein with an altered structure. This change makes the protein more prone to misfolding and aggregation, accelerating the disease and often leading to an earlier onset of symptoms.
Another genetic factor is the duplication or triplication of the SNCA gene, where a person has extra copies. This leads to the overproduction of the normal alpha-synuclein protein, increasing the likelihood of aggregation even without structural mutations. Individuals with SNCA triplications tend to have a more severe and earlier disease onset compared to those with duplications, demonstrating that protein quantity is a significant factor in Parkinson’s development.
Researching Treatments Focused on Alpha-Synuclein
Given its role in the disease, alpha-synuclein is a primary target for new Parkinson’s therapies. One major area of investigation is immunotherapy, which uses the body’s immune system to target and clear the abnormal protein. This includes active approaches, like vaccines that teach the immune system to attack misfolded alpha-synuclein, and passive approaches that use manufactured antibodies.
Another strategy involves small molecules designed to interfere with the aggregation process. Some of these experimental drugs aim to prevent the initial misfolding of alpha-synuclein or to break up aggregates once they have formed. By halting the formation of toxic oligomers and fibrils, these treatments could slow the progression of neuronal damage.
Researchers are also exploring ways to reduce the production of the alpha-synuclein protein. Since genetic evidence shows that an excess of the protein can cause the disease, therapies that lower its expression are being tested. Other approaches focus on enhancing the cell’s natural disposal systems, like autophagy, to help clear out toxic aggregates. These strategies are promising avenues for developing treatments that could modify the course of Parkinson’s disease.