Alpha-synuclein is a small protein found abundantly in nerve cells within the human brain. This naturally occurring protein plays a role in the intricate machinery that allows our brains to function properly.
The Normal Shape of Alpha-Synuclein
In its healthy, natural state, alpha-synuclein is characterized as an intrinsically disordered protein. This means it lacks a fixed, stable three-dimensional structure when it is freely floating in the cellular fluid. Instead, it remains highly flexible, constantly changing its shape, which allows it to interact with various cellular components. When alpha-synuclein associates with cellular membranes, such as those surrounding vesicles that store neurotransmitters, it can adopt a more ordered, helical structure.
Alpha-synuclein is found most prominently in presynaptic terminals, the ends of neurons responsible for releasing neurotransmitters. Its normal functions include involvement in neurotransmitter release, a process called exocytosis, which is fundamental for communication between neurons. It may also play a role in synaptic plasticity, the ability of synapses to strengthen or weaken over time, a basis for learning and memory.
When Alpha-Synuclein Changes Shape
Normally flexible alpha-synuclein can misfold from its disordered state into abnormal, rigid structures. This process begins when individual protein units, or monomers, clump together, forming small aggregates called oligomers. These intermediate structures are thought to be particularly harmful to brain cells.
These smaller clumps can then grow larger, eventually forming insoluble, thread-like structures known as amyloid fibrils. These fibrils are characterized by a high content of beta-sheet structures, making them very stable and resistant to degradation. The exact triggers for this misfolding are not fully understood but are believed to involve a combination of factors, including genetic mutations in the alpha-synuclein gene, environmental factors, and the natural process of aging.
Why Shape Matters in Brain Health
Abnormal alpha-synuclein shapes and aggregation have significant consequences for brain health, contributing to neurodegenerative conditions known as synucleinopathies. These include Parkinson’s disease, Lewy body dementia, and multiple system atrophy. In these conditions, misfolded alpha-synuclein aggregates accumulate within neurons, forming characteristic inclusions called Lewy bodies and Lewy neurites.
These aggregates disrupt cellular processes, leading to neuronal dysfunction and cell death. They impact mitochondria, the cell’s energy producers, causing mitochondrial dysfunction. Aggregates also impair waste clearance systems, such as the ubiquitin-proteasome system and autophagy, leading to a buildup of damaged proteins and organelles.
Misfolded alpha-synuclein can spread from one brain cell to another, inducing normal alpha-synuclein in healthy cells to misfold and aggregate. This prion-like spread contributes to disease progression throughout the brain. This propagation, along with neuroinflammation, exacerbates neuronal damage and disease progression.
Targeting Shape for New Therapies
Understanding alpha-synuclein’s different shapes, both healthy and aggregated, guides new therapeutic strategies. One approach aims to prevent initial misfolding, stabilizing its normal, disordered state or preventing its transition into toxic oligomers. Researchers explore small molecules that bind to alpha-synuclein and inhibit aggregation.
Another strategy focuses on clearing existing alpha-synuclein aggregates from the brain. This includes immunotherapies, which use antibodies designed to recognize and remove misfolded alpha-synuclein or prevent its cell-to-cell spread. These antibodies might target specific forms, such as oligomers or fibrils, to enhance their clearance by the immune system.
Gene therapies are also being investigated, aiming to reduce alpha-synuclein production in the brain, thereby decreasing aggregation likelihood. These diverse approaches, including small molecules, immunotherapies, and gene therapies, are in preclinical research or clinical trials, offering hope for future synucleinopathy treatments.