Alpha-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. Alpha-synuclein is mainly present at the presynaptic terminals in the neuronal mitochondria and comprises of 1% of total cytosolic protein in the nervous system. It is mainly related to neurodegenerative diseases in humans.
Function
Even though it is well known that the aggregation of this protein is related to neurodegenerative disorders, the regular function of the protein is not well understood. However, literature suggests that there exists a strong genetic link between the protein and 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 with time. Excessive expression of alpha-synuclein is noted to delay degeneration that happens due to loss of CSPα, thus giving alpha synuclein a chaperone like function where this protein works with the CSPα in assembly of the SNARE complex, which is a type of large protein complex that deals with the fusion synaptic vesicles with the neurons in the brain. Therefore it is said that the main function of the alpha-synuclein is to regulate the neurotransmitter release.
Structure
The alpha-synuclein (1-121) default scene is about 14 kDa fibril constituted by two protofilaments of 121 residues [1]. The presence of many ꞵ-sheet induce a Greek-key motif of 99Å diameter [2]. Indeed, There are 8 Beta-strands interrupted by glycines, between the residues 42 to about 102 [3].
Two structures coincide thanks to the presence of hydrophobic (pink) and hydrophilic(grey) regions. A hydrophobic intra-molecular core between the two protofilaments is formed by alanines, valines and one isoleucine. A hydrophilic channel contains majority of threonines. To stabilize the protein in an aqueous solution, there are solvent exposed charged residues : Lysine and glutamic acid.
Disease
One of the main characteristics of Neurodegenerative disorders is the loss of the protective capacity surrounding the neurons or the gain of the toxic proteins. The mechanism by which the neuronal damage occurs is due to specific mutations, or other alterations of the synaptic proteins. Recently, two main hypotheses have been developed surrounding Parkinson's disease research. Firstly, the missense mutation of the α-synuclein gene is a rare genetic disorder that causes Parkinson's disease. Secondly, the α-synuclein protein is the main component of Lewy bodies and Lewy neurites which are defining pathological characteristics of all Parkinson's disease cases. <ref>https://doi.org/10.1038/35081564<ref> Parkinson's disease is characterized by the accumulation of Lewy bodies in the substantia nigra, where Lewy bodies contain a build-up of α-synuclein found within the cells that contribute to the disease <ref>PMID: 9546347<ref>
Relevance
Besides being of key importance in reducing the degeneration caused due to the loss of CSPα, the alpha-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 association of the protein to the membrane dependent on GTP, but the mechanism of this regulation is not unclear as the function of the alpha synuclein is not totally understood. Alpha-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 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.
- ↑ Guerrero-Ferreira R, Taylor NMI, Mona D, Ringler P, Lauer ME, Riek R, Britschgi M, Stahlberg H. Cryo-EM structure of alpha-synuclein fibrils. Elife. 2018 Jul 3;7. pii: 36402. doi: 10.7554/eLife.36402. PMID:29969391 doi:https://dx.doi.org/10.7554/eLife.36402
- ↑ Li B, Ge P, Murray KA, Sheth P, Zhang M, Nair G, Sawaya MR, Shin WS, Boyer DR, Ye S, Eisenberg DS, Zhou ZH, Jiang L. Cryo-EM of full-length alpha-synuclein reveals fibril polymorphs with a common structural kernel. Nat Commun. 2018 Sep 6;9(1):3609. doi: 10.1038/s41467-018-05971-2. PMID:30190461 doi:https://dx.doi.org/10.1038/s41467-018-05971-2
- ↑ Guerrero-Ferreira R, Taylor NMI, Mona D, Ringler P, Lauer ME, Riek R, Britschgi M, Stahlberg H. Cryo-EM structure of alpha-synuclein fibrils. Elife. 2018 Jul 3;7. pii: 36402. doi: 10.7554/eLife.36402. PMID:29969391 doi:https://dx.doi.org/10.7554/eLife.36402
