Alpha-synuclein is a protein abundant in the human brain, concentrated at the tips of neurons in structures called presynaptic terminals. These terminals release chemical messengers, known as neurotransmitters, allowing nerve cells to communicate. While found in smaller amounts in the heart and muscles, its prevalence in the brain highlights its role in the nervous system.
Normal Function of Alpha-Synuclein
In its healthy state, alpha-synuclein is a player in regulating the release of neurotransmitters at the synapse. It helps manage the lifecycle of synaptic vesicles, the tiny sacs that store and release these chemical messengers. This function is aided by its flexibility; it is an “intrinsically disordered protein,” meaning it lacks a fixed three-dimensional structure.
This lack of a rigid shape allows alpha-synuclein to change its conformation and interact with a wide variety of other molecules and cellular structures, particularly the membranes of synaptic vesicles. Upon binding to these membranes, a part of the alpha-synuclein protein adopts a more organized, helical structure. This interaction is believed to be involved in the clustering of synaptic vesicles, which can influence the readiness and timing of neurotransmitter release. This dynamic nature is central to its normal operation within the presynaptic terminal.
Beyond neurotransmission, alpha-synuclein is involved in other cellular processes. It helps maintain the function of mitochondria, the cell’s energy-producing centers. It also participates in regulating gene expression within the neuron’s nucleus, which can affect cellular activities like DNA repair.
The Process of Misfolding and Aggregation
Problems with alpha-synuclein begin when it deviates from its normally unfolded, soluble state. Individual alpha-synuclein proteins, or monomers, can misfold into an incorrect shape, causing them to become “sticky” and clump together. The process starts when these misfolded monomers bind to each other, forming small, soluble clusters known as oligomers.
These oligomers are considered the most toxic form of alpha-synuclein, as they can disrupt cellular processes and damage the membranes of mitochondria. As aggregation continues, oligomers act as seeds, recruiting healthy monomers to misfold and join the clump. This chain reaction leads to the formation of larger, insoluble protein structures.
The aggregation process culminates in long, thread-like structures called amyloid fibrils. These fibrils are stable and resistant to the cell’s protein disposal systems. Over time, these fibrils and other cellular debris accumulate inside the neuron to form dense inclusions known as Lewy bodies, a pathological hallmark of certain neurodegenerative diseases.
This cascade represents a breakdown in cellular quality control, which normally identifies and clears misfolded proteins. When this system fails due to genetics, environmental stress, or aging, the aggregation process can escalate. This ultimately leads to cellular dysfunction and the death of the neuron.
Associated Neurodegenerative Diseases
The accumulation of misfolded alpha-synuclein links a group of progressive neurological disorders known as synucleinopathies. The specific disease that develops depends on which cells and brain regions are most affected by the protein aggregates. The primary conditions in this category are Parkinson’s disease, Dementia with Lewy Bodies, and Multiple System Atrophy.
In Parkinson’s disease, alpha-synuclein aggregates predominantly affect and destroy dopamine-producing neurons in a part of the brain called the substantia nigra. This region is heavily involved in controlling movement, and its degeneration leads to the motor symptoms of Parkinson’s, such as resting tremor, rigidity, and slowness of movement (bradykinesia). The pathology often extends to other brain regions, causing non-motor symptoms like constipation or sleep disorders.
Dementia with Lewy Bodies (DLB) is characterized by the widespread presence of Lewy bodies in the cerebral cortex, the brain’s outer layer for higher cognitive functions. This leads to symptoms that overlap with Parkinson’s and Alzheimer’s disease, including fluctuating cognition and visual hallucinations. In contrast, Multiple System Atrophy (MSA) is distinct because alpha-synuclein aggregates accumulate primarily within glial cells rather than neurons. This leads to severe autonomic dysfunction, like problems with blood pressure, alongside parkinsonism or impaired coordination.
Genetic and Environmental Influences
The misfolding of alpha-synuclein involves a combination of genetic predispositions and environmental factors. For a small percentage of individuals, the cause is directly genetic. Mutations in the SNCA gene, which provides instructions for making the protein, are a known cause of familial, early-onset Parkinson’s disease.
Certain point mutations, such as the A53T mutation, can make the resulting protein more prone to aggregation. In other cases, the issue is a duplication or even triplication of the entire SNCA gene. This leads to an overproduction of the normal alpha-synuclein protein, and this excess quantity increases the likelihood that proteins will clump together, initiating the disease process. The more extra copies of the gene a person has, the earlier the disease tends to start and the more severe it is.
Most cases of synucleinopathies are sporadic, meaning they occur without a known hereditary link. In these instances, environmental exposures are thought to contribute to the risk. Research has explored links between these diseases and long-term exposure to substances including pesticides, industrial chemicals, and heavy metals. Such exposures may place stress on neurons, disrupting cellular processes that prevent protein misfolding.
Targeting Alpha-Synuclein for Diagnosis and Treatment
Alpha-synuclein’s role in these diseases makes it a focus for developing new diagnostic tools and treatments. A key diagnostic tool is the seed amplification assay (SAA). This sensitive test can detect minuscule amounts of misfolded alpha-synuclein in biological samples, such as cerebrospinal fluid or skin biopsies. The assay works by adding normal alpha-synuclein to a sample; if misfolded “seeds” are present, they trigger a rapid, detectable chain reaction of aggregation.
This technology allows for an earlier and more accurate diagnosis of synucleinopathies, sometimes before major symptoms appear. It can help distinguish between different neurodegenerative disorders that may present with similar initial symptoms. Researchers are also working on imaging agents that could one day allow for the visualization of alpha-synuclein aggregates in the living brain using positron emission tomography (PET).
On the therapeutic front, several strategies are being investigated to combat the harmful effects of alpha-synuclein. One area is immunotherapy, which uses the body’s immune system to target and clear the protein aggregates. This involves developing vaccines or administering laboratory-produced antibodies to remove the toxic clumps. Other approaches focus on developing small-molecule drugs designed to stabilize the protein’s normal shape or to inhibit the aggregation process.