8xwd
From Proteopedia
Croy-EM structure of alpha synuclein fibril with EGCG
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 PubMedalpha-Syn fibrils, a key pathological hallmark of Parkinson's disease, is closely associated with disease initiation and progression. Several small molecules are found to bind or dissolve alpha-syn fibrils, offering potential therapeutic applications. Here, an innovative optical tweezers-based, fluorescence-combined approach is developed to probe the mechanical characteristics of alpha-syn fibrils at the single-molecule level. When subjected to axial stretching, local deformation within alpha-syn fibrils appeared at forces above 50 pN. These structural alternations occurred stepwise and are irreversible, suggesting unfolding of individual alpha-syn molecules or subdomains. Additionally, alpha-syn fibrils exhibits high heterogeneity in lateral disruption, with rupture force ranging from 50 to 500 pN. The impact of different compounds on the structure and mechanical features of alpha-syn fibrils is further examined. Notably, epigallocatechin gallate (EGCG) generally attenuates the rupture force of fibrils by wedging into the N-terminal polar groove and induces fibril dissociation. Conversely, copper chlorophyllin A (CCA) attaches to four different sites wrapping around the fibril core, reinforcing the stability of the fibril against rupture forces. The work offers an effective method for characterizing single-fibril properties and bridges compound-induced structural alternations with mechanical response. These insights are valuable for understanding amyloid fibril mechanics and their regulation by small molecules. Single-Molecule Insight Into alpha-Synuclein Fibril Structure and Mechanics Modulated by Chemical Compounds.,Li X, Bi L, Zhang S, Xu Q, Xia W, Tao Y, Wu S, Li Y, Le W, Kang W, Li D, Sun B, Liu C Adv Sci (Weinh). 2025 Feb 14:e2416721. doi: 10.1002/advs.202416721. PMID:39951335[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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