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CryoEM structure of recombinant DeltaN7 alpha-synuclein in PBSCryoEM structure of recombinant DeltaN7 alpha-synuclein in PBS
Structural highlights
DiseaseSYUA_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. FunctionSYUA_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 PubMedAmyloid formation by alpha-synuclein (alphaSyn) occurs in Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies. Deciphering the residues that regulate alphaSyn amyloid fibril formation will not only provide mechanistic insight but may also reveal targets to prevent and treat disease. Previous investigations have identified several regions of alphaSyn to be important in the regulation of amyloid formation, including the non-amyloid-beta component (NAC), P1 region (residues 36 to 42), and residues in the C-terminal domain. Recent studies have also indicated the importance of the N-terminal region of alphaSyn for both its physiological and pathological roles. Here, the role of residues 2 to 7 in the N-terminal region of alphaSyn is investigated in terms of their ability to regulate amyloid fibril formation in vitro and in vivo. Deletion of these residues (alphaSynDeltaN7) slows the rate of fibril formation in vitro and reduces the capacity of the protein to be recruited by wild-type (alphaSynWT) fibril seeds, despite cryo-EM showing a fibril structure consistent with those of full-length alphaSyn. Strikingly, fibril formation of alphaSynDeltaN7 is not induced by liposomes, despite the protein binding to liposomes with similar affinity to alphaSynWT. A Caenorhabditis elegans model also showed that alphaSynDeltaN7::YFP forms few puncta and lacks motility and lifespan defects typified by expression of alphaSynWT::YFP. Together, the results demonstrate the involvement of residues 2 to 7 of alphaSyn in amyloid formation, revealing a target for the design of amyloid inhibitors that may leave the functional role of the protein in membrane binding unperturbed. Residues 2 to 7 of alpha-synuclein regulate amyloid formation via lipid-dependent and lipid-independent pathways.,Dewison KM, Rowlinson B, Machin JM, Crossley JA, Thacker D, Wilkinson M, Ulamec SM, Khan GN, Ranson NA, van Oosten-Hawle P, Brockwell DJ, Radford SE Proc Natl Acad Sci U S A. 2024 Aug 20;121(34):e2315006121. doi: , 10.1073/pnas.2315006121. Epub 2024 Aug 12. PMID:39133842[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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