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From Proteopedia
Structure of recombinantly assembled A53E alpha-synuclein fibrils
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 PubMedSynucleinopathies like Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple systems atrophy (MSA), have the same pathologic feature of misfolded alpha-synuclein protein (alpha-syn) accumulation in the brain. PD patients who carry alpha-syn hereditary mutations tend to have earlier onset and more severe clinical symptoms than sporadic PD patients. Therefore, revealing the effect of hereditary mutations to the alpha-syn fibril structure can help us understand these synucleinopathies' structural basis. Here, we present a 3.38 A cryo-electron microscopy structure of alpha-synuclein fibrils containing the hereditary A53E mutation. The A53E fibril is symmetrically composed of two protofilaments, similar to other fibril structures of WT and mutant alpha-synuclein. The new structure is distinct from all other synuclein fibrils, not only at the interface between proto-filaments, but also between residues packed within the same proto-filament. A53E has the smallest interface with the least buried surface area among all alpha-syn fibrils, consisting of only two contacting residues. Within the same protofilament, A53E reveals distinct residue re-arrangement and structural variation at a cavity near its fibril core. Moreover, the A53E fibrils exhibit slower fibril formation and lower stability compared to WT and other mutants like A53T and H50Q, while also demonstrate strong cellular seeding in alpha-synuclein biosensor cells and primary neurons. In summary, our study aims to highlight structural differences - both within and between the protofilaments of A53E fibrils - and interpret fibril formation and cellular seeding of alpha-synuclein pathology in disease, which could further our understanding of the structure-activity relationship of alpha-synuclein mutants. Cryo-EM structure of amyloid fibril formed by alpha-synuclein hereditary A53E mutation reveals a distinct protofilament interface.,Sun C, Zhou K, DePaola P 4th, Shin WS, Hillyer T, Sawaya MR, Zhu R, Peng C, Zhou ZH, Jiang L J Biol Chem. 2023 Apr;299(4):104566. doi: 10.1016/j.jbc.2023.104566. Epub 2023 , Mar 5. PMID:36871760[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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