9c5r
Structure of recombinantly assembled alpha-synuclein variant 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 PubMedAmyloidoses are predominantly associated with the accumulation of persistent aggregates of a particular protein. For example, the protein alpha-synuclein characteristically aggregates in Parkinson's disease (PD), while amyloid beta and tau deposits are associated with Alzheimer's disease (AD). However, alpha-synuclein-positive inclusions have been reportedly found in some tauopathies, and vice versa; tau-positive inclusions can be found in synucleinopathies. This suggests that there may be coexistence or crosstalk between these proteinopathies. This coexistence suggests that the simultaneous presence of these misfolded proteins may amplify pathogenic mechanisms. However, the crosstalk between these two types of proteopathies remains poorly understood. We now determine the structure of alpha-synuclein fibrils that directly promote tau aggregation by cryogenic electron microscopy. Helical reconstruction at 2.6 A resolution reveals a new alpha-synuclein fibril polymorph we term "strain B"; its core is unique, incorporating both the N- and C-termini of alpha-synuclein. The design of peptides meant to inhibit the formation of this structure demonstrates that the C-terminal domain fragment (D105-E115) of alpha-synuclein is critical for the formation of "strain B" fibrils and may play a key role in its interaction with tau. We hypothesize that the unique structure of pathological alpha-synuclein significantly contributes to tau co-aggregation and plays a role in the intricate interactions among Alzheimer's, Parkinson's, and other neurodegenerative diseases. These findings open new avenues for drug targeting, discovery, and improve our understanding of neurodegenerative pathology. Structural basis of a distinct alpha-synuclein strain that promotes tau inclusion in neurons.,Sun C, Zhou K, DePaola P 4th, Li C, Lee VMY, Zhou ZH, Peng C, Jiang L J Biol Chem. 2025 Feb 25;301(4):108351. doi: 10.1016/j.jbc.2025.108351. PMID:40015644[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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