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<StructureSection load='6flt' size='340' side='right'caption='[[6flt]], [[Resolution|resolution]] 3.42Å' scene=''> | <StructureSection load='6flt' size='340' side='right'caption='[[6flt]], [[Resolution|resolution]] 3.42Å' scene=''> | ||
| - | + | 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 comprises of 1% of the total cytosolic protein in the nervous system. It is mainly related to neurodegenerative diseases in humans. | |
== Function == | == 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, the 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 | + | 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, the 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 α-synuclein is noted to delay degeneration that happens due to loss of CSPα, thus giving α-synuclein a chaperone-like function where this protein works with the CSPα in the 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 α-synuclein is to regulate the neurotransmitter release. |
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Parkinson's disease (PD) is the most common neurodegenerative disorder affecting more than 10 Million Worldwide <ref>(https://www.parkinson.org/Understanding-Parkinsons/Statistics)</ref>. 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, it has been found that 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 (PD) is the most common neurodegenerative disorder affecting more than 10 Million Worldwide <ref>(https://www.parkinson.org/Understanding-Parkinsons/Statistics)</ref>. 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, it has been found that 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>. | ||
==Mechanism of aggregation== | ==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 <ref>PMID: 9546347<ref> 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 the in 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. The role of α-synuclein in the pathogenesis of PD is mediated through the formation of the 58-83 KD complex that contains α-synuclein and 14-3-3 protein, which inhibits BCL-BAD protein complex responsible for the inhibition of Apoptosis.<ref>doi: 10.1126/scitranslmed.3002566</ref> However, 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). | + | 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 <ref>PMID: 9546347<ref>. 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 the in 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. The role of α-synuclein in the pathogenesis of PD is mediated through the formation of the 58-83 KD complex that contains α-synuclein and 14-3-3 protein, which inhibits BCL-BAD protein complex responsible for the inhibition of Apoptosis.<ref>doi: 10.1126/scitranslmed.3002566</ref> However, 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 == | == Relevance == | ||
| - | Besides being of key importance in reducing the degeneration caused due to the loss of CSPα, the | + | 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 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. |
Revision as of 15:23, 17 January 2020
| This Sandbox is Reserved from 25/11/2019, through 30/9/2020 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1091 through Sandbox Reserved 1115. |
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References
Bendor, J. T., Logan, T. P., & Edwards, R. H. (2013). The function of α-synuclein. Neuron, 79(6), 1044–1066. doi:10.1016/j.neuron.2013.09.004 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866954/ Cold Spring Harb Perspect Med 2012;4:a009399, Stefanis L.a-Synuclein in Parkinson’s Disease . https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281589/pdf/cshperspectmed-PKD-a009399.pdf UniProtKB - P37840 (SYUA_HUMAN) https://www.uniprot.org/uniprot/P37840
- ↑ 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:http://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:http://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:http://dx.doi.org/10.7554/eLife.36402
- ↑ 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:http://dx.doi.org/10.7554/eLife.36402
- ↑ 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:http://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:http://dx.doi.org/10.1038/s41467-018-05971-2
- ↑ (https://www.parkinson.org/Understanding-Parkinsons/Statistics)
- ↑ https://doi.org/10.1038/35081564
- ↑ PMID: 9546347<ref>. 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 the in 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. The role of α-synuclein in the pathogenesis of PD is mediated through the formation of the 58-83 KD complex that contains α-synuclein and 14-3-3 protein, which inhibits BCL-BAD protein complex responsible for the inhibition of Apoptosis.<ref>doi: 10.1126/scitranslmed.3002566</li></ol></ref>
