Alpha-synuclein is a protein found in the human brain, particularly abundant within neurons. This small protein plays a part in the processes that allow brain cells to communicate effectively. While its exact physiological functions are still being investigated, it is recognized in both healthy brain activity and its association with certain neurological disorders when it undergoes abnormal changes.
Normal Roles in the Body
Alpha-synuclein is abundant throughout the brain, especially at the presynaptic terminals of neurons. These terminals are specialized regions where neurotransmitters are released to communicate with other neurons. In this location, alpha-synuclein interacts with phospholipids and other proteins to support synaptic function.
The protein is involved in the regulation of synaptic vesicle trafficking, which involves tiny sacs (synaptic vesicles) that store neurotransmitters. It helps in processes such as the docking, priming, and fusion of these vesicles to release neurotransmitters into the synaptic cleft. Alpha-synuclein also influences the recycling of synaptic vesicles after they have released their contents, ensuring efficient signal transmission.
The precise effect of alpha-synuclein on neurotransmitter release, whether it facilitates or inhibits it, remains a topic of discussion. However, it is clear that it helps regulate the availability of vesicles for neurotransmission and can modulate the release of dopamine, a neurotransmitter involved in movement, motivation, and reward. The protein’s interaction with the SNARE complex, a group of proteins involved in vesicle fusion, highlights its role in neuronal communication.
When Alpha-Synuclein Goes Wrong
Under healthy conditions, alpha-synuclein typically exists as a monomer, a single, unfolded protein, or as a helically folded form when bound to membranes. However, in certain pathological states, this protein can undergo a conformational change, misfolding into a beta-sheet-rich structure. This altered shape makes it prone to aggregation, where multiple misfolded proteins form clumps.
These aggregates can form various structures, from small, soluble oligomers and protofibrils to larger, insoluble fibrils. These insoluble clumps are the main components of abnormal inclusions found within neurons, known as Lewy bodies and Lewy neurites. The accumulation of these aggregates is thought to disrupt normal cellular functions and can ultimately lead to neuronal dysfunction and cell death.
Research suggests that these misfolded alpha-synuclein aggregates can spread from one brain cell to another in a “prion-like” manner. In this process, the abnormal protein acts as a template, inducing normally folded alpha-synuclein in neighboring cells to misfold and aggregate. This cell-to-cell transmission of pathology is believed to contribute to the progressive spread of neurodegeneration throughout the brain. Such aggregates interfere with cellular processes including the ubiquitin-proteasome system and lysosomal pathways, which are responsible for protein degradation and waste removal. Additionally, these abnormal forms can negatively impact mitochondrial function, reducing energy production and increasing oxidative stress within neurons.
Associated Neurological Conditions
Alpha-synuclein pathology is a characteristic of a group of neurodegenerative disorders collectively known as synucleinopathies. These conditions include Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA), each presenting with distinct clinical symptoms due to the specific brain regions affected by alpha-synuclein aggregates.
In Parkinson’s Disease, the accumulation of alpha-synuclein in Lewy bodies is prominent in the dopamine-producing neurons of the substantia nigra, a brain region involved in movement control. The presence of these aggregates is strongly associated with the progressive degeneration and loss of these dopamine neurons, which leads to the characteristic motor symptoms of PD, such as tremor, rigidity, and slow movement. The aggregates are also thought to interfere with synaptic function, impairing neurotransmitter release and contributing to neuronal dysfunction.
Dementia with Lewy Bodies is characterized by the widespread presence of Lewy bodies and Lewy neurites throughout the brain, including the cortex. This extensive pathology directly impacts cognitive function, leading to symptoms like fluctuating attention, problems with executive function, and recurrent visual hallucinations. The small alpha-synuclein aggregates found at presynaptic terminals, rather than just the larger Lewy bodies, are thought to be a primary cause of the synaptic dysfunction observed in DLB, contributing to the cognitive decline.
Multiple System Atrophy is distinct in that alpha-synuclein aggregates primarily accumulate in glial cells (oligodendrocytes) rather than neurons. These aggregates form glial cytoplasmic inclusions (GCIs) and are found in various brain regions, including the cerebellum, brainstem, and basal ganglia. The presence of GCIs leads to the degeneration of oligodendrocytes and the myelin sheath they produce, resulting in widespread neurological dysfunction. This pathology underlies the diverse symptoms of MSA, which can include autonomic dysfunction (e.g., blood pressure regulation issues), cerebellar ataxia (impaired coordination and balance), and parkinsonism (motor symptoms similar to PD).