Alpha-synuclein is a protein found throughout the brain, playing a part in normal brain activity. While generally beneficial, this protein can undergo modifications that alter its behavior. One such modification, known as phosphorylation, involves the addition of a small chemical group to the protein. This change can transform alpha-synuclein into a form implicated in neurodegenerative processes.
Understanding Alpha-Synuclein
Alpha-synuclein is an abundant protein located primarily within neurons, particularly at the presynaptic terminals where nerve cells communicate. It is considered an intrinsically disordered protein, meaning it does not have a fixed three-dimensional structure in its normal, soluble state. This protein is involved in several functions related to synaptic communication, including the regulation of neurotransmitter release and the trafficking of synaptic vesicles. Synaptic vesicles are tiny sacs that store and release neurotransmitters, chemical messengers that transmit signals between neurons. Alpha-synuclein’s interaction with these vesicles helps ensure the proper flow of information within the brain.
The Process of Phosphorylation
Phosphorylation is a common biological process where a phosphate group is added to a molecule, such as a protein. This addition typically occurs on specific amino acid residues within the protein. The enzymes responsible for adding these phosphate groups are called kinases, while phosphatases remove them. This reversible modification can significantly alter a protein’s shape, activity, or interactions, often acting like a molecular switch. The change in conformation can influence its ability to bind to other molecules or perform specific tasks within the cell.
The Role of Phosphorylated Alpha-Synuclein in Disease
When alpha-synuclein becomes phosphorylated, particularly at a specific site called Serine 129 (pS129), its behavior changes dramatically. In a healthy brain, only a small percentage of alpha-synuclein is phosphorylated at this site, typically 4% or less. However, in certain neurodegenerative conditions, pS129 alpha-synuclein can constitute up to 90% of the protein found in abnormal aggregates. This increased phosphorylation at Serine 129 promotes the protein’s misfolding and aggregation.
Misfolded alpha-synuclein proteins clump together, forming insoluble fibrils. These aggregates are a hallmark of several neurodegenerative diseases. They can accumulate within neurons, forming characteristic inclusions known as Lewy bodies, or extend into neuronal processes, creating Lewy neurites. These aggregated forms are toxic to neurons, impairing their function and leading to cell death. Their accumulation disrupts essential cellular processes, including synaptic function and transport of cellular components, contributing to progressive degeneration.
Neurodegenerative Conditions Associated with Phosphorylated Alpha-Synuclein
Aggregated, phosphorylated alpha-synuclein defines a group of disorders known as synucleinopathies. The three conditions in this group are Parkinson’s Disease (PD), Lewy Body Dementia (LBD), and Multiple System Atrophy (MSA). These diseases share the common pathological feature of pS129 alpha-synuclein accumulation, though aggregate distribution varies, leading to different clinical symptoms.
In Parkinson’s Disease, phosphorylated alpha-synuclein aggregates contribute to the loss of dopamine-producing neurons, primarily in the substantia nigra. This neuronal loss links to motor symptoms like tremor, rigidity, and slow movement. For Lewy Body Dementia, widespread accumulation of phosphorylated alpha-synuclein in the brain’s outer layers associates with cognitive fluctuations, visual hallucinations, and parkinsonism. In Multiple System Atrophy, these aggregates are found in neurons and glial cells, leading to severe autonomic dysfunction, motor control issues, and cerebellar symptoms.