7c1d: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Cryo-EM structure of the hE46K cross-seeded hWT alpha-synuclein fibril== | ==Cryo-EM structure of the hE46K cross-seeded hWT alpha-synuclein fibril== | ||
<StructureSection load='7c1d' size='340' side='right'caption='[[7c1d]]' scene=''> | <StructureSection load='7c1d' size='340' side='right'caption='[[7c1d]], [[Resolution|resolution]] 3.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7C1D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7C1D FirstGlance]. <br> | <table><tr><td colspan='2'>[[7c1d]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7C1D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7C1D FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7c1d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7c1d OCA], [https://pdbe.org/7c1d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7c1d RCSB], [https://www.ebi.ac.uk/pdbsum/7c1d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7c1d ProSAT]</span></td></tr> | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SNCA, NACP, PARK1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7c1d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7c1d OCA], [https://pdbe.org/7c1d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7c1d RCSB], [https://www.ebi.ac.uk/pdbsum/7c1d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7c1d ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[[https://www.uniprot.org/uniprot/SYUA_HUMAN SYUA_HUMAN]] Note=Genetic alterations of SNCA resulting in aberrant polymerization into fibrils, are associated with several neurodegenerative diseases (synucleinopathies). SNCA fibrillar aggregates represent the major non A-beta component of Alzheimer disease amyloid plaque, and a major component of Lewy body inclusions. They are also found within Lewy body (LB)-like intraneuronal inclusions, glial inclusions and axonal spheroids in neurodegeneration with brain iron accumulation type 1. Defects in SNCA are the cause of Parkinson disease type 1 (PARK1) [MIM:[https://omim.org/entry/168601 168601]]. A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features.<ref>PMID:9197268</ref> <ref>PMID:9462735</ref> <ref>PMID:14755719</ref> Defects in SNCA are the cause of Parkinson disease type 4 (PARK4) [MIM:[https://omim.org/entry/605543 605543]]. A complex neurodegenerative disorder with manifestations ranging from typical Parkinson disease to dementia with Lewy bodies. Clinical features include parkinsonian symptoms (tremor, rigidity, postural instability and bradykinesia), dementia, diffuse Lewy body pathology, autonomic dysfunction, hallucinations and paranoia. Defects in SNCA are the cause of dementia Lewy body (DLB) [MIM:[https://omim.org/entry/127750 127750]]. A neurodegenerative disorder clinically characterized by mental impairment leading to dementia, parkinsonism, often with fluctuating cognitive function, visual hallucinations, falls, syncopal episodes, and sensitivity to neuroleptic medication. Brainstem or cortical intraneuronal accumulations of aggregated proteins (Lewy bodies) are the only essential pathologic features. Patients may also have hippocampal and neocortical senile plaques, sometimes in sufficient number to fulfill the diagnostic criteria for Alzheimer disease. | |||
== Function == | |||
[[https://www.uniprot.org/uniprot/SYUA_HUMAN SYUA_HUMAN]] May be involved in the regulation of dopamine release and transport. Induces fibrillization of microtubule-associated protein tau. Reduces neuronal responsiveness to various apoptotic stimuli, leading to a decreased caspase-3 activation. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Heterozygous point mutations of alpha-synuclein (alpha-syn) have been linked to the early onset and rapid progression of familial Parkinson's diseases (fPD). However, the interplay between hereditary mutant and wild-type (WT) alpha-syn and its role in the exacerbated pathology of alpha-syn in fPD progression are poorly understood. Here, we find that WT mice inoculated with the human E46K mutant alpha-syn fibril (hE46K) strain develop early-onset motor deficit and morphologically different alpha-syn aggregation compared with those inoculated with the human WT fibril (hWT) strain. By using cryo-electron microscopy, we reveal at the near-atomic level that the hE46K strain induces both human and mouse WT alpha-syn monomers to form the fibril structure of the hE46K strain. Moreover, the induced hWT strain inherits most of the pathological traits of the hE46K strain as well. Our work suggests that the structural and pathological features of mutant strains could be propagated by the WT alpha-syn in such a way that the mutant pathology would be amplified in fPD. | |||
Wild-type alpha-synuclein inherits the structure and exacerbated neuropathology of E46K mutant fibril strain by cross-seeding.,Long H, Zheng W, Liu Y, Sun Y, Zhao K, Liu Z, Xia W, Lv S, Liu Z, Li D, He KW, Liu C Proc Natl Acad Sci U S A. 2021 May 18;118(20). pii: 2012435118. doi:, 10.1073/pnas.2012435118. PMID:33972418<ref>PMID:33972418</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7c1d" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Liu C]] | [[Category: Liu, C]] | ||
[[Category: Sun | [[Category: Sun, Y P]] | ||
[[Category: Zhao K]] | [[Category: Zhao, K]] | ||
[[Category: Amyloid fibril]] | |||
[[Category: Protein fibril]] | |||
Revision as of 13:20, 18 May 2022
Cryo-EM structure of the hE46K cross-seeded hWT alpha-synuclein fibrilCryo-EM structure of the hE46K cross-seeded hWT alpha-synuclein fibril
Structural highlights
Disease[SYUA_HUMAN] Note=Genetic alterations of SNCA resulting in aberrant polymerization into fibrils, are associated with several neurodegenerative diseases (synucleinopathies). SNCA fibrillar aggregates represent the major non A-beta component of Alzheimer disease amyloid plaque, and a major component of Lewy body inclusions. They are also found within Lewy body (LB)-like intraneuronal inclusions, glial inclusions and axonal spheroids in neurodegeneration with brain iron accumulation type 1. Defects in SNCA are the cause of Parkinson disease type 1 (PARK1) [MIM:168601]. A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features.[1] [2] [3] Defects in SNCA are the cause of Parkinson disease type 4 (PARK4) [MIM:605543]. A complex neurodegenerative disorder with manifestations ranging from typical Parkinson disease to dementia with Lewy bodies. Clinical features include parkinsonian symptoms (tremor, rigidity, postural instability and bradykinesia), dementia, diffuse Lewy body pathology, autonomic dysfunction, hallucinations and paranoia. Defects in SNCA are the cause of dementia Lewy body (DLB) [MIM:127750]. A neurodegenerative disorder clinically characterized by mental impairment leading to dementia, parkinsonism, often with fluctuating cognitive function, visual hallucinations, falls, syncopal episodes, and sensitivity to neuroleptic medication. Brainstem or cortical intraneuronal accumulations of aggregated proteins (Lewy bodies) are the only essential pathologic features. Patients may also have hippocampal and neocortical senile plaques, sometimes in sufficient number to fulfill the diagnostic criteria for Alzheimer disease. Function[SYUA_HUMAN] May be involved in the regulation of dopamine release and transport. Induces fibrillization of microtubule-associated protein tau. Reduces neuronal responsiveness to various apoptotic stimuli, leading to a decreased caspase-3 activation. Publication Abstract from PubMedHeterozygous point mutations of alpha-synuclein (alpha-syn) have been linked to the early onset and rapid progression of familial Parkinson's diseases (fPD). However, the interplay between hereditary mutant and wild-type (WT) alpha-syn and its role in the exacerbated pathology of alpha-syn in fPD progression are poorly understood. Here, we find that WT mice inoculated with the human E46K mutant alpha-syn fibril (hE46K) strain develop early-onset motor deficit and morphologically different alpha-syn aggregation compared with those inoculated with the human WT fibril (hWT) strain. By using cryo-electron microscopy, we reveal at the near-atomic level that the hE46K strain induces both human and mouse WT alpha-syn monomers to form the fibril structure of the hE46K strain. Moreover, the induced hWT strain inherits most of the pathological traits of the hE46K strain as well. Our work suggests that the structural and pathological features of mutant strains could be propagated by the WT alpha-syn in such a way that the mutant pathology would be amplified in fPD. Wild-type alpha-synuclein inherits the structure and exacerbated neuropathology of E46K mutant fibril strain by cross-seeding.,Long H, Zheng W, Liu Y, Sun Y, Zhao K, Liu Z, Xia W, Lv S, Liu Z, Li D, He KW, Liu C Proc Natl Acad Sci U S A. 2021 May 18;118(20). pii: 2012435118. doi:, 10.1073/pnas.2012435118. PMID:33972418[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||