Alpha-synuclein is a small, highly abundant protein found throughout the brain, primarily concentrated within neurons. This protein is naturally unstructured and soluble, performing its function in the healthy nervous system. Alpha-synuclein is the focus of intense scientific study due to its central involvement in neurodegenerative disorders. The accumulation and misfolding of this protein is a defining characteristic of these diseases, driving the pathological changes observed in the brain.
Function of Alpha-Synuclein in Healthy Cells
In healthy neurons, alpha-synuclein is predominantly localized to the presynaptic terminal, the specialized tip of the nerve cell responsible for communication. The protein associates closely with the membranes of synaptic vesicles, which are sacs that store and release chemical messengers called neurotransmitters. When alpha-synuclein binds to these curved membranes, its unstructured form folds into an alpha-helical shape, necessary for its proper function.
Alpha-synuclein acts as a regulator of synaptic transmission by managing the supply of neurotransmitters available for release. It contributes to the organization and mobility of synaptic vesicles, influencing how they are clustered within the terminal. The protein also plays a role in the final steps of neurotransmitter release by interacting with the cellular machinery that fuses the vesicle to the cell membrane. This regulation of vesicle dynamics helps ensure that communication between neurons is sustained, especially during periods of high electrical activity.
The Pathological Transition: Misfolding and Aggregation
The transition to a toxic agent begins when the balance between alpha-synuclein production and clearance is disrupted. The protein, which normally exists as a single, unfolded unit, starts to misfold and accumulate. This process involves a structural change, shifting the protein from its soluble state into structures prone to self-association.
The first step is the formation of soluble, intermediate structures known as oligomers. These small clusters of misfolded alpha-synuclein are believed to be the most damaging species, initiating toxicity before larger clumps form. Oligomers impair various cellular functions, including damaging mitochondria, disrupting internal transport systems, and compromising cell membrane integrity.
As misfolding continues, oligomers grow larger and reorganize into insoluble, thread-like structures called amyloid fibrils. These fibrils bundle together to form large, dense deposits within the cytoplasm of neurons and sometimes glial cells. These large clumps are the pathological hallmark known as Lewy bodies, or Lewy neurites in the slender extensions of neurons. Lewy bodies may represent the cell’s attempt to sequester the toxic oligomers into a less harmful deposit. These misfolded aggregates also exhibit a “prion-like” behavior, seeding the misfolding of normal alpha-synuclein in neighboring cells and spreading the pathology throughout the brain.
The Synucleinopathies: Diseases Driven by Protein Accumulation
The neurodegenerative conditions linked to the accumulation of misfolded alpha-synuclein are collectively known as synucleinopathies. These diseases share a common molecular pathology but manifest with distinct clinical symptoms based on where the protein aggregates are concentrated. The three primary disorders are Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA).
Parkinson’s Disease (PD)
In PD, the pathology begins deep within the brain, particularly in the substantia nigra, which produces dopamine. The destruction of these neurons causes characteristic motor symptoms, including tremors, rigidity, and slowed movement. Lewy bodies are found in these affected brainstem areas, driving the motor impairment that defines the condition.
Dementia with Lewy Bodies (DLB)
DLB is characterized by a more widespread distribution of aggregates, involving regions closer to the brain’s surface, such as the cerebral cortex. This cortical involvement leads to significant cognitive symptoms, including fluctuating attention, visual hallucinations, and impaired executive function. Although patients may exhibit parkinsonism, the cognitive decline typically appears earlier and is more prominent than in PD.
Multiple System Atrophy (MSA)
MSA is a distinct synucleinopathy where aggregates are found primarily in glial cells, specifically oligodendrocytes, rather than just neurons. MSA is often associated with severe, early-onset problems related to the autonomic nervous system, controlling involuntary functions like blood pressure. The disease also causes parkinsonism and cerebellar dysfunction, leading to coordination and balance difficulties.
Research Directions for Therapeutic Intervention
Current research into synucleinopathies is heavily focused on developing strategies to interrupt the pathological process at various stages, moving beyond merely treating symptoms. Efforts are concentrated on three main approaches:
Preventing Misfolding
One major area involves developing small molecules that can prevent the initial misfolding and aggregation of the protein. Researchers are exploring ways to stabilize the healthy, non-toxic forms of alpha-synuclein, such as its monomeric state, to stop the progression toward toxic oligomers.
Reducing Protein Production
A second strategy aims to reduce the total amount of alpha-synuclein protein being produced within neurons. This is achieved through the use of antisense oligonucleotides (ASOs), which interfere with the genetic instructions for making the protein. Lowering the overall protein burden decreases the likelihood of it misfolding and accumulating.
Enhancing Aggregate Clearance
Another focus is on enhancing the brain’s natural ability to clear existing aggregates from both inside and outside the cells. Inside the cell, researchers investigate ways to boost the autophagy-lysosomal pathway, the cell’s internal waste disposal system. Outside the cell, immunotherapy uses antibodies to recognize and remove extracellular aggregates, preventing their spread between neurons.