α-synuclein is a protein encoded by the SNCA gene in humans and belongs to the family of synuclein proteins that also consist of beta and gamma- synuclein. It is present in large quantities in the brain and in comparatively smaller quantities in other tissues in the body. α-synuclein is mainly present at the presynaptic terminals in the neuronal mitochondria and consists of 1% of the total cytosolic protein in the nervous system. Recently, it became evident that α-synuclein is directly linked to neurodegenerative diseases in humans [1].
Structure
The is about 14 kDa fibril constituted by two protofilaments of 121 residues [2]. The presence of many ꞵ-sheet induce a Greek-key motif of 99 Å diameter [3]. Indeed, There are 8 , between the residues 42 to about 102 forming the ꞵ-arch [4]. These glycines help the folding of the molecule by their small size. The ꞵ-arch is stabilized by .
Two structures coincide thanks to the presence of . A hydrophobic intra-molecular core between the two protofilaments is formed by [5]. Residues from 54 to 75 form a which contains majority of threonines and glutamic acid[6]. To stabilize the protein in an aqueous solution, there are solvent-exposed charged residues: .
Fibrils form by stacking a . It is a helix with a pitch of 920 Å[7].
Function
Even though it is well known that the aggregation of α-synuclein is related to neurodegenerative disorders, the actual function of the protein remains unknown. Nonetheless, the literature suggests that there exists a strong genetic link between α-synuclein and synaptic degeneration that arises from the loss of certain chaperone proteins called presynaptic chaperone cysteine string proteins (CSPα). This loss of CSPα does not affect the transmission of the neuronal signals immediately but progresses over time. However, excessive expression of α-synuclein is noted to delay synaptic degeneration that happens due to the loss of CSPα. As a result, α-synuclein is suggested to have a chaperone-like function, where it works with the CSPα in the assembly of the SNARE complex. More precisely, the latter is a large protein complex that is responsible for the fusion of synaptic vesicles with the neurons in the brain. That being said, there are exist several hypotheses around the role of α-synuclein protein, but studies suggest that its function is related to the regulation of synaptic vesicles, which in turn reduce the effect of synaptic recycling and neurotransmitter release [8][9].
Clinical Significance
α-synuclein can be described as an unstructured soluble protein, which lacks three-dimensional folding that proteins undergo after synthesis. Nevertheless, the clinical significance of α-synuclein protein lies behind the formation of insoluble fibrils characterized by Lewy bodies which can be found in Parkinson's disease (PD), dementia with Lewy bodies, multiple system atrophy [10], as well as Alzheimer's disease. [11]. Moreover, Parkinson's disease is the most common neurodegenerative disorder affecting more than 10 Million Worldwide [12]. As mentioned before, one of the main characteristics of Parkinson's disease is the aggregation of Lewy bodies. The aggregation mechanism of α-synuclein is still uncertain, however, there have been several hypotheses published in the literature.[13].
Mechanism of aggregation
Parkinson's disease is characterized by the accumulation of Lewy bodies in the substantia nigra, a region in the midbrain responsible for motor control, where Lewy bodies contain a build-up of α-synuclein found within the cells that contribute to the disease [14]. Lewy Bodies are cytoplasmic inclusion made of primarily α-synuclein protein, and may also contain other proteins such as; ubiquitin, Tau proteins. The structure of α-synuclein; N-terminal domain, C-terminal domain, and a hydrophobic core (NAC) suggests an aggregation pathway due to the unfolded nature of the protein. A recent study published by Science Translational Medicine Journal, suggests that a covalent modification such as Serine-129 phosphorylation in α-synuclein, as well as hydrophobic interactions specifically located at the NAC domain of α-synuclein, allows for the polymerization of different α-synuclein protein into an anti-parallel β-sheet conformation permitting the formation of fibrils. Another hypothesis suggests the role of α-synuclein in the loss of dopaminergic neurons functions in PD, which is mediated through the formation of the 54-83 KD complex that contains aggregates of α-synuclein and 14-3-3 protein, which inhibits BCL-BAD protein complex responsible for the inhibition of Apoptosis in dopamine neurons in the midbrain.[15][16]. All in all, it is important to know that the pathway discussed above is one of many hypotheses for the role of α-synuclein in Parkinson's Disease (PD).
Relevance
Besides being of key importance in reducing the degeneration caused due to the loss of CSPα, the α-synuclein is also believed to be related to various other proteins that regulate its activity. An example of this is the interaction of synuclein with synphilin that promotes its aggregation, the details of this interaction however are still not clear. Recent studies also suggest that a small protein GTPase rab3a is believed to be regulating the association of the protein to the membrane dependent on GTP, but the mechanism of this regulation is not unclear as the function of the α-synuclein is not totally understood. α-synuclein is also believed to have an impact on protein degradation, cytoskeletal interrelations and complex 1 inhibition in mitochondria inducing oxidative stress that results in neuronal death. It also plays an important role in the regulation of dopamine neurotransmission. Therefore, owing to the role that this protein plays, especially in neurodegenerative disorders, various therapeutic measures related to this protein are being studied.[17]
