Alpha-Synuclein and α-Synucleinopathies

What is Alpha-Synuclein?

Alpha-synuclein (α-syn) is a small, natively unfolded protein encoded by the SNCA gene. It is predominantly expressed in the brain, particularly at the presynaptic terminals of neurons.

Normal Functions

In a healthy nervous system, α-syn plays a crucial role in:

• Neurotransmitter Release: It is involved in the regulation of synaptic vesicle trafficking and neurotransmitter release, facilitating proper neuronal communication.
• Synaptic Plasticity: α-syn contributes to the maintenance of synaptic plasticity, which is essential for learning and memory.

Mutations and Pathological Effects

Mutations in the SNCA gene can lead to the misfolding and aggregation of α-syn, resulting in the formation of toxic protein aggregates. These aggregates can disrupt normal cellular processes and lead to neuronal death.

Aggregation in Cells

The aggregation process begins with the accumulation of monomeric α-syn, which then forms oligomeric intermediates. These oligomers further aggregate into amyloid fibrils, which cluster into larger inclusions known as Lewy bodies and Lewy neurites. These aggregates are toxic to neurons and contribute to neurodegeneration.

Associated Diseases

α-Synucleinopathies are a group of neurodegenerative disorders characterized by the abnormal accumulation of α-syn. The primary diseases associated with α-syn include:

• Parkinson’s Disease (PD): α-syn aggregates are a hallmark of PD, leading to the loss of dopaminergic neurons in the substantia nigra.
• Dementia with Lewy Bodies (DLB): Characterized by cognitive decline and the presence of Lewy bodies in the brain.
• Multiple System Atrophy (MSA): A rare neurodegenerative disorder with widespread α-syn accumulation in oligodendrocytes.
• Other Conditions: α-syn aggregates have also been found in Alzheimer’s disease and other neurodegenerative conditions.

References: 

1.https://alpha-synuclein.net/aggregation/

2.https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-020-00368-6

3.https://www.physio-pedia.com/Alpha-Synuclein_%28%CE%B1-syn%29