6ct7 | pdb_00006ct7
Fab of anti-a-synuclein antibody BIIB054 in complex with acetylated a-synuclein peptide (1-10)
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 PubMedAggregation of alpha-synuclein (alpha-syn) is neuropathologically and genetically linked to Parkinson's disease (PD). Since stereotypic cell-to-cell spreading of alpha-syn pathology is believed to contribute to disease progression, immunotherapy with antibodies directed against alpha-syn is considered a promising therapeutic approach for slowing disease progression. Here we report the identification, binding characteristics, and efficacy in PD mouse models of the human-derived alpha-syn antibody BIIB054, which is currently under investigation in a Phase 2 clinical trial for PD. BIIB054 was generated by screening human memory B-cell libraries from healthy elderly individuals. Epitope mapping studies conducted using peptide scanning, X-ray crystallography, and mutagenesis show that BIIB054 binds to alpha-syn residues 1-10. BIIB054 is highly selective for aggregated forms of alpha-syn with at least an 800-fold higher apparent affinity for fibrillar versus monomeric recombinant alpha-syn and a strong preference for human PD brain tissue. BIIB054 discriminates between monomers and oligomeric/fibrillar forms of alpha-syn based on high avidity for aggregates, driven by weak monovalent affinity and fast binding kinetics. In efficacy studies in three different mouse models with intracerebrally inoculated preformed alpha-syn fibrils, BIIB054 treatment attenuated the spreading of alpha-syn pathology, rescued motor impairments, and reduced the loss of dopamine transporter density in dopaminergic terminals in striatum. The preclinical data reported here provide a compelling rationale for clinical development of BIIB054 for the treatment and prevention of PD. Development of an aggregate-selective, human-derived alpha-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models.,Weihofen A, Liu Y, Arndt JW, Huy C, Quan C, Smith BA, Baeriswyl JL, Cavegn N, Senn L, Su L, Marsh G, Auluck PK, Montrasio F, Nitsch RM, Hirst WD, Cedarbaum JM, Pepinsky RB, Grimm J, Weinreb PH Neurobiol Dis. 2018 Oct 28;124:276-288. doi: 10.1016/j.nbd.2018.10.016. PMID:30381260[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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