Sandbox Reserved 1109: Difference between revisions

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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 <ref>DOI 10.1016/j.neuron.2013.09.004</ref>.  
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 <ref>DOI 10.1016/j.neuron.2013.09.004</ref>.  


== Function ==
== Structure ==


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 <ref>DOI 10.1016/j.neuron.2013.09.004</ref><ref> DOI: 10.1016/j.neuron.2009.12.023</ref>.
The <scene name='82/829362/Default_scene/4'>α-synuclein (1-121)</scene> is about 14 kDa fibril constituted by two protofilaments of 121 residues <ref>DOI 10.7554/eLife.36402</ref>. The presence of many ꞵ-sheet induce a Greek-key motif of 99 Å diameter <ref>DOI 10.1038/s41467-018-05971-2</ref>. Indeed, There are 8 <scene name='82/829362/beta-strands/7'>beta-strands interrupted by glycines</scene>, between the residues 42 to about 102 forming the ꞵ-arch <ref>DOI 10.7554/eLife.36402</ref>. These glycines help the folding of the molecule by their small size. The ꞵ-arch is stabilized by <scene name='82/829362/Hydrogen_bond/1'>hydrogen bonds N65-G68 and Q79-G86</scene>.


Two structures coincide thanks to the presence of <scene name='82/829362/Hydrophobic/3'>hydrophobic (red) and hydrophilic(blue) regions</scene>. A hydrophobic intra-molecular core between the two protofilaments is formed by <scene name='82/829362/Hydrophobic_ala_val_ile/3'>alanines, valines and one isoleucine</scene><ref>DOI 10.7554/eLife.36402</ref>. Residues from 54 to 75  form a <scene name='82/829362/Hydrophilic_channel/5'>hydrophilic channel</scene> which contains majority of threonines and glutamic acid<ref>DOI 10.7554/eLife.36402</ref>. To stabilize the protein in an aqueous solution, there are solvent-exposed charged residues: <scene name='82/829362/Hydrophobic_glu_lys/2'>Lysine and glutamic acid</scene>.


== Structure ==
Fibrils form by stacking a <scene name='82/829362/Rod_polymorph/1'>rod polymorph</scene>. It is a helix with a pitch of 920 Å<ref>DOI 10.1038/s41467-018-05971-2</ref>.


The <scene name='82/829362/Default_scene/4'>alpha-synuclein (1-121)</scene> is about 14 kDa fibril constituted by two protofilaments of 121 residues <ref>DOI 10.7554/eLife.36402</ref>. The presence of many ꞵ-sheet induce a Greek-key motif of 99 Å diameter <ref>DOI 10.1038/s41467-018-05971-2</ref>. Indeed, There are 8 <scene name='82/829362/beta-strands/7'>beta-strands interrupted by glycines</scene>, between the residues 42 to about 102 forming the ꞵ-arch <ref>DOI 10.7554/eLife.36402</ref>. These glycines help the folding of the molecule by their small size. The ꞵ-arch is stabilized by <scene name='82/829362/Hydrogen_bond/1'>hydrogen bonds N65-G68 and Q79-G86</scene>.
== Function ==


Two structures coincide thanks to the presence of <scene name='82/829362/Hydrophobic/3'>hydrophobic (red) and hydrophilic(blue) regions</scene>. A hydrophobic intra-molecular core between the two protofilaments is formed by <scene name='82/829362/Hydrophobic_ala_val_ile/3'>alanines, valines and one isoleucine</scene><ref>DOI 10.7554/eLife.36402</ref>. Residues from 54 to 75  form a <scene name='82/829362/Hydrophilic_channel/5'>hydrophilic channel</scene> which contains majority of threonines and glutamic acid<ref>DOI 10.7554/eLife.36402</ref>. To stabilize the protein in an aqueous solution, there are solvent-exposed charged residues: <scene name='82/829362/Hydrophobic_glu_lys/2'>Lysine and glutamic acid</scene>.  
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 <ref>DOI 10.1016/j.neuron.2013.09.004</ref><ref> DOI: 10.1016/j.neuron.2009.12.023</ref>.


Fibrils form by stacking a <scene name='82/829362/Rod_polymorph/1'>rod polymorph</scene>. It is a helix with a pitch of 920 Å<ref>DOI 10.1038/s41467-018-05971-2</ref>.


== Disease ==
== Clinical Significance ==
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==
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