Alpha-synuclein is a small protein abundant in the brain, with smaller amounts in other tissues like the heart and muscles. It is primarily found at presynaptic terminals of neurons, structures vital for nerve cell communication. While associated with neurodegenerative conditions, its exact normal functions are still being investigated. Its precise roles in both healthy brain function and disease pathology continue to be uncovered.
The Normal Role of α-Synuclein
In healthy brains, alpha-synuclein supports the function and integrity of synapses, the junctions where neurons transmit signals. It is involved in neurotransmitter release, the process by which neurons send chemical messages. Alpha-synuclein interacts with phospholipids and other proteins, facilitating the movement and release of synaptic vesicles, tiny sacs that store and release neurotransmitters.
The protein also contributes to synaptic plasticity, the ability of synapses to strengthen or weaken over time, which is fundamental for learning and memory. Alpha-synuclein is believed to affect the spatial organization of synaptic vesicle pools within the presynaptic terminal. This supports the long-term operation of the nervous system.
When α-Synuclein Goes Wrong
Under normal conditions, alpha-synuclein exists in a soluble, unfolded state. However, it can misfold and aggregate into insoluble clumps. These abnormal aggregates can take various forms, including small soluble oligomers and larger, fibrillar structures. When these aggregates accumulate inside neurons, they often form Lewy bodies, a hallmark of several neurodegenerative diseases.
Misfolding can be influenced by genetic mutations in the SNCA gene, which encodes alpha-synuclein, or by aging. Once misfolding begins, it can proceed in a “prion-like” manner, where misfolded alpha-synuclein induces healthy proteins to also misfold and aggregate, contributing to the spread of pathology. These toxic aggregates disrupt cellular functions, including impairing cellular transport, causing mitochondrial dysfunction, altering the ubiquitin-proteasome system, and triggering inflammation.
Conditions Linked to α-Synuclein Dysfunction
Dysfunction and aggregation of alpha-synuclein are central to a group of neurodegenerative conditions known as synucleinopathies. These disorders share abnormal alpha-synuclein accumulation within brain cells, leading to distinct clinical symptoms. The primary synucleinopathies include Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA).
Parkinson’s Disease (PD)
In Parkinson’s Disease, alpha-synuclein pathology primarily affects dopaminergic neurons in the substantia nigra, leading to dopamine loss. This deficiency results in motor symptoms such as tremors, muscle rigidity, slow movement (bradykinesia), and balance problems. Lewy bodies are found in neuronal cell bodies and processes throughout the brain and peripheral nervous system in PD.
Dementia with Lewy Bodies (DLB)
Dementia with Lewy Bodies is characterized by widespread alpha-synuclein aggregates in the cerebral cortex, limbic system, and hippocampus. This contributes to fluctuating cognitive impairment, including variations in attention, recurrent visual hallucinations, and parkinsonian motor symptoms.
Multiple System Atrophy (MSA)
Multiple System Atrophy involves alpha-synuclein aggregation predominantly in oligodendrocytes, cells that produce myelin. Pathology in MSA affects regions like the olivopontocerebellar, nigrostriatal, and autonomic systems. This leads to a combination of symptoms such as parkinsonism, cerebellar ataxia (problems with coordination and balance), and severe autonomic dysfunction affecting blood pressure, bladder control, and digestion.
Advancing Therapies for α-Synucleinopathies
Current research and therapeutic strategies for synucleinopathies target various aspects of alpha-synuclein pathology.
Reducing Production
One approach aims to reduce alpha-synuclein production, as increased levels are linked to disease. This involves gene therapy strategies, such as antisense oligonucleotides or RNA interference, to decrease SNCA gene expression.
Preventing Misfolding and Aggregation
Another strategy prevents alpha-synuclein misfolding and aggregation into toxic forms. This includes developing small molecules that inhibit harmful oligomer and fibril formation, or stabilizing normal, non-aggregating protein forms. Enhancing the clearance of toxic alpha-synuclein aggregates from inside and outside cells is also an area of research. Immunotherapy, using antibodies to target and remove extracellular alpha-synuclein, is a promising avenue undergoing clinical trials.
Blocking Spread
Further efforts block the “prion-like” spread of misfolded alpha-synuclein between cells. This might involve inhibiting the uptake of extracellular aggregates by neighboring cells or blocking specific cell surface receptors. While challenges remain, these diverse approaches offer hope for developing disease-modifying therapies that could slow or halt synucleinopathy progression.