Sandbox Reserved 1109: Difference between revisions

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== 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 <ref>doi:10.1007/s00401-002-0596-7,/ref>, as well as Alzheimer's disease. <ref>DOI:10.1007/s00401-002-0596-7</ref>. Moreover, Parkinson's disease is the most common neurodegenerative disorder affecting more than 10 Million Worldwide <ref>(https://www.parkinson.org/Understanding-Parkinsons/Statistics)</ref>. ~~as discussed~~ 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.<ref>https://doi.org/10.1038/35081564</ref>.

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 <ref>doi:10.1007/s00401-002-0596-7</ref>, as well as Alzheimer's disease. <ref>DOI:10.1007/s00401-002-0596-7</ref>. Moreover, Parkinson's disease is the most common neurodegenerative disorder affecting more than 10 Million Worldwide <ref>(https://www.parkinson.org/Understanding-Parkinsons/Statistics)</ref>. 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.<ref>https://doi.org/10.1038/35081564</ref>.

==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 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.<ref>https://doi.org/10.1038/s41420-018-0125-7</ref> <ref>doi: 10.1126/scitranslmed.3002566</ref>. 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).

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 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.<ref>https://doi.org/10.1038/s41420-018-0125-7</ref><ref>doi: 10.1126/scitranslmed.3002566</ref>. 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 ==

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 == 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 <ref>doi:10.1007/s00401-002-0596-7,/ref>, as well as Alzheimer's disease. <ref>DOI:10.1007/s00401-002-0596-7</ref>. Moreover, Parkinson's disease is the most common neurodegenerative disorder affecting more than 10 Million Worldwide <ref>(https://www.parkinson.org/Understanding-Parkinsons/Statistics)</ref>. as discussed 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.<ref>https://doi.org/10.1038/35081564</ref>.
+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 <ref>doi:10.1007/s00401-002-0596-7</ref>, as well as Alzheimer's disease. <ref>DOI:10.1007/s00401-002-0596-7</ref>. Moreover, Parkinson's disease is the most common neurodegenerative disorder affecting more than 10 Million Worldwide <ref>(https://www.parkinson.org/Understanding-Parkinsons/Statistics)</ref>. 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.<ref>https://doi.org/10.1038/35081564</ref>.
 ==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 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.<ref>https://doi.org/10.1038/s41420-018-0125-7</ref> <ref>doi: 10.1126/scitranslmed.3002566</ref>. 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).
+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 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.<ref>https://doi.org/10.1038/s41420-018-0125-7</ref><ref>doi: 10.1126/scitranslmed.3002566</ref>. 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 ==