9rb3
A53T alpha-synuclein fibril - Type 1
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-Synuclein conformational strains provide a potential explanation for the clinical and pathological differences among synucleinopathies such as Parkinson's disease and multiple system atrophy. However, how distinct alpha-synuclein strains arise remains unknown. Here, we observed conformational heterogeneity between individual preparations of alpha-synuclein pre-formed fibrils (PFFs) generated by polymerizing wild-type or A53T-mutant human alpha-synuclein under identical conditions. Moreover, we found that alpha-synuclein aggregates formed spontaneously in the brains of a transgenic synucleinopathy mouse model are conformationally diverse. Propagation of stochastically formed PFF- and brain-derived alpha-synuclein strains in mice initiated several distinct synucleinopathies. The conformational diversity of alpha-synuclein aggregates across PFF preparations and between individual mice demonstrates that alpha-synuclein can spontaneously form multiple self-propagating strains within an identical environment. This suggests that stochastic misfolding into distinct aggregate structures drives the emergence of alpha-synuclein strains and reveals that the intrinsic variability of common synucleinopathy research tools must be considered when designing and interpreting experiments. Stochastic misfolding drives the emergence of distinct alpha-synuclein strains.,So RWL, Frieg B, Camino JD, Situ C, Metri MN, Silver NRG, Li LY, Mao A, Stuart E, Schroder GF, Watts JC Neuron. 2026 Feb 27:S0896-6273(26)00040-1. doi: 10.1016/j.neuron.2026.01.014. PMID:41763203[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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