Alpha-synuclein is a protein that is abundant in the human brain and is also found in smaller amounts in other tissues like the heart and muscles. Encoded by the SNCA gene, this protein is a plentiful component of the nervous system. In the brain, alpha-synuclein is primarily located at the tips of nerve cells, known as neurons. It exists in a naturally unfolded state under normal conditions, meaning it doesn’t have a fixed, rigid structure, which allows its conformation to change depending on its environment.
The Normal Function of Alpha-Synuclein
Alpha-synuclein is predominantly found at presynaptic terminals, the part of the neuron responsible for sending signals to other neurons. Its location suggests a role in neurotransmitter release. Neurotransmitters are chemical messengers that neurons use to communicate, and they are stored in small sacs called synaptic vesicles. Alpha-synuclein helps regulate the release of these chemicals, including dopamine.
The protein interacts with synaptic vesicles and is involved in their trafficking, which is the process of moving them to the correct location for release. By assisting in the clustering and maintenance of synaptic vesicle pools, alpha-synuclein helps ensure that a ready supply of neurotransmitters is available when a neuron needs to fire a signal. It also plays a part in remodeling the cell membrane during the release and recycling of these vesicles.
Misfolding and Aggregation
For reasons that may include genetic mutations or environmental factors, this protein can begin to misfold. Instead of maintaining its functional shape, it adopts a beta-sheet structure. This conformation makes it more likely to stick to other alpha-synuclein proteins.
This misfolding event triggers a chain reaction. Single units of the protein, called monomers, start to clump together, first forming small, toxic clusters known as oligomers. These oligomers are considered harmful to the neuron. Over time, these smaller clusters continue to grow, forming larger, insoluble strands called fibrils.
These thread-like fibrils are the primary component of abnormal structures that appear inside brain cells, called Lewy bodies. The formation of these aggregates disrupts the normal function of the neuron, creating cellular debris that the cell may not be able to clear away. This progression from a functional protein to disruptive clumps is a feature of several neurodegenerative diseases.
Connection to Neurodegenerative Diseases
The accumulation of misfolded alpha-synuclein is a pathological hallmark of a group of neurodegenerative disorders known as synucleinopathies. These diseases are characterized by the presence of alpha-synuclein aggregates within neurons and other brain cells. The most well-known synucleinopathies include Parkinson’s disease, Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA).
In these conditions, the buildup of alpha-synuclein clumps contributes directly to neuronal dysfunction and eventual cell death. In Parkinson’s disease, for example, the loss of dopamine-producing neurons in a part of the brain called the substantia nigra leads to motor symptoms like tremors and rigidity. In DLB, the aggregates are more widespread, affecting areas of the brain involved in thinking and memory, which results in cognitive impairment and hallucinations.
The presence of these aggregates interferes with numerous cellular processes, including mitochondrial function, and can trigger neuroinflammation, where the brain’s immune cells become overactive. The spread of these aggregates from one neuron to another in a prion-like process helps explain the progressive nature of these diseases. The specific type of neuron affected and the location of the aggregates in the brain determine the specific symptoms and diagnosis.
Therapeutic Research and Targets
Given alpha-synuclein’s role in disease, scientists are exploring several therapeutic strategies. The first strategy focuses on clearing the alpha-synuclein aggregates that have already formed. This is primarily being pursued through immunotherapy, which uses antibodies designed to recognize and bind to the misfolded protein, tagging it for removal by the body’s immune system.
A second strategy aims to prevent the initial misfolding and aggregation of the protein. This involves the development of small molecule inhibitors that can stabilize the normal, unfolded shape of alpha-synuclein or interfere with its ability to clump together. By preventing the formation of toxic oligomers and fibrils, these potential treatments hope to halt the disease process before significant damage occurs.
A third approach seeks to reduce the overall amount of alpha-synuclein protein being produced. Since genetic duplications of the SNCA gene can lead to the disease, researchers are investigating ways to lower the expression of this gene. This can be achieved through genetic approaches like RNA interference, which can target and degrade the messenger RNA that serves as the blueprint for making the alpha-synuclein protein, thereby reducing its synthesis.