Synuclein proteins are a family of small, soluble proteins found primarily in the nervous system. While their exact physiological functions are still being investigated, their significance extends to several neurodegenerative diseases. Understanding synuclein proteins involves exploring their different types, their normal roles within cells, and the consequences of their misfolding and aggregation.
Types and Normal Roles of Synuclein
There are three main types of synuclein proteins: alpha-synuclein, beta-synuclein, and gamma-synuclein. Alpha-synuclein is the most studied variant due to its strong association with neurodegenerative diseases. This small protein, composed of 140 amino acids, is abundant in the brain, particularly in the presynaptic terminals of neurons where neurotransmitters are released.
Alpha-synuclein regulates synaptic vesicle trafficking and the release of neurotransmitters, chemical messengers for neuronal communication. It interacts with membranes, potentially helping maintain the curvature of synaptic vesicles and influencing their movement and recycling. This function is important for efficient signal transmission and coordinated movement.
Beta-synuclein is also found in presynaptic terminals and inhibits alpha-synuclein aggregation, suggesting a protective role. Gamma-synuclein is present in the peripheral nervous system and the retina. It has been linked to macrophage recruitment to damaged areas and scar tissue production. Its absence in the central nervous system has been associated with decreased memory in animal models.
Misfolding and Aggregation
Under normal conditions, alpha-synuclein exists as an unfolded protein. However, in disease states, alpha-synuclein can misfold and aggregate into abnormal structures. This process begins with individual, correctly folded proteins (monomers) transforming into incorrect shapes.
These misfolded proteins stick together, forming small, soluble clumps called oligomers. As aggregation continues, these oligomers assemble into larger, insoluble structures known as fibrils. These fibrils have a characteristic beta-sheet structure. The accumulation of these misfolded alpha-synuclein oligomers and fibrils within cells is considered toxic.
The soluble oligomeric forms of alpha-synuclein are harmful to neurons, causing cellular dysfunction, oxidative stress, and impaired energy production. While fibrils are the main component of pathological inclusions in the brain, they can also release these toxic oligomeric species. The concept of “prion-like spread” suggests that misfolded alpha-synuclein can transfer from one neuron to another, inducing the misfolding of normal alpha-synuclein in the recipient cell and propagating the pathology through neuronal networks.
Synucleinopathies
Synucleinopathies are a group of neurodegenerative disorders characterized by the pathological accumulation of misfolded alpha-synuclein proteins in the brain. These abnormal protein deposits can form structures called Lewy bodies within neuronal cell bodies and Lewy neurites in neuronal processes. Alpha-synuclein also aggregates in glial cells, forming glial cytoplasmic inclusions in some cases.
Parkinson’s Disease (PD) is the most common synucleinopathy, marked by the loss of dopamine-producing neurons in the substantia nigra. The accumulation of alpha-synuclein in Lewy bodies is a hallmark of PD, contributing to motor symptoms such as tremors, rigidity, and slow movement. Patients with PD may also experience non-motor symptoms like depression, anxiety, and sleep disorders, and some may develop dementia later.
Dementia with Lewy Bodies (DLB) is another synucleinopathy, often presenting with fluctuating cognitive impairment, visual hallucinations, and parkinsonian features. In DLB, Lewy bodies are more widespread in the brain’s cortex, contributing to distinct cognitive symptoms. Patients with DLB frequently experience delusions and disinhibition in addition to depression and anxiety.
Multiple System Atrophy (MSA) is characterized by alpha-synuclein accumulation in neurons and glial cells, particularly oligodendrocytes. MSA manifests with a combination of symptoms, including parkinsonism (often less responsive to standard Parkinson’s medications), cerebellar ataxia (problems with coordination and balance), and severe autonomic dysfunction, such as issues with blood pressure regulation and urinary control. The specific brain regions affected by alpha-synuclein pathology can vary between these disorders, contributing to their distinct clinical presentations despite the shared underlying protein pathology.