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A short motif in the N-terminal region of ?-synuclein is critical for both aggregation and function.

ABSTRACT: Aggregation of human ?-synuclein (?Syn) is linked to Parkinson's disease (PD) pathology. The central region of the ?Syn sequence contains the non-amyloid ?-component (NAC) crucial for aggregation. However, how NAC flanking regions modulate ?Syn aggregation remains unclear. Using bioinformatics, mutation and NMR, we identify a 7-residue sequence, named P1 (residues 36-42), that controls ?Syn aggregation. Deletion or substitution of this 'master controller' prevents aggregation at pH 7.5 in vitro. At lower pH, P1 synergises with a sequence containing the preNAC region (P2, residues 45-57) to prevent aggregation. Deleting P1 (?P1) or both P1 and P2 (??) also prevents age-dependent ?Syn aggregation and toxicity in C. elegans models and prevents ?Syn-mediated vesicle fusion by altering the conformational properties of the protein when lipid bound. The results highlight the importance of a master-controller sequence motif that controls both ?Syn aggregation and function-a region that could be targeted to prevent aggregation in disease.

SUBMITTER: Doherty CPA

PROVIDER: S-EPMC7100612 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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A short motif in the N-terminal region of α-synuclein is critical for both aggregation and function.

Doherty Ciaran P A CPA Ulamec Sabine M SM Maya-Martinez Roberto R Good Sarah C SC Makepeace Jemma J Khan G Nasir GN van Oosten-Hawle Patricija P Radford Sheena E SE Brockwell David J DJ

Nature structural & molecular biology 20200309 3

Aggregation of human α-synuclein (αSyn) is linked to Parkinson's disease (PD) pathology. The central region of the αSyn sequence contains the non-amyloid β-component (NAC) crucial for aggregation. However, how NAC flanking regions modulate αSyn aggregation remains unclear. Using bioinformatics, mutation and NMR, we identify a 7-residue sequence, named P1 (residues 36-42), that controls αSyn aggregation. Deletion or substitution of this 'master controller' prevents aggregation at pH 7.5 in vitro. ...[more]

PMID: 32157247

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Project description:Synucleinopathies, including Parkinson's disease (PD), Lewy body dementia (LBD), Alzheimer's disease with amygdala restricted Lewy bodies (AD/ALB), and multiple system atrophy (MSA) comprise a spectrum of neurodegenerative disorders characterized by the presence of distinct pathological α-synuclein (αSyn) inclusions. Experimental and pathological studies support the notion that αSyn aggregates contribute to cellular demise and dysfunction with disease progression associated with a prion-like spread of αSyn aggregates via conformational templating. The initiating event(s) and factors that contribute to diverse forms of synucleinopathies remain poorly understood. A major post-translational modification of αSyn associated with pathological inclusions is a diverse array of specific truncations within the carboxy terminal region. While these modifications have been shown experimentally to induce and promote αSyn aggregation, little is known about their disease-, region- and cell type specific distribution. To this end, we generated a series of monoclonal antibodies specific to neo-epitopes in αSyn truncated after residues 103, 115, 119, 122, 125, and 129. Immunocytochemical investigations using these new tools revealed striking differences in the αSyn truncation pattern between different synucleinopathies, brain regions and specific cellular populations. In LBD, neuronal inclusions in the substantia nigra and amygdala were positive for αSyn cleaved after residues 103, 119, 122, and 125, but not 115. In contrast, in the same patients' brain αSyn cleaved at residue 115, as well as 103, 119 and 122 were abundant in the dorsal motor nucleus of the vagus. In patients with AD/ALB, these modifications were only weakly or not detected in amygdala αSyn inclusions. αSyn truncated at residues 103, 115, 119, and 125 was readily present in MSA glial cytoplasmic inclusions, but 122 cleaved αSyn was only weakly or not present. Conversely, MSA neuronal pathology in the pontine nuclei was strongly reactive to the αSyn x-122 neo-epitope but did not display any reactivity for αSyn 103 cleavage. These studies demonstrate significant disease-, region- and cell type specific differences in carboxy terminal αSyn processing associated with pathological inclusions that likely contributes to their distinct strain-like prion properties and promotes the diversity displayed in the degrees of these insidious diseases.

Dataset Information

A short motif in the N-terminal region of ?-synuclein is critical for both aggregation and function.

Publications

A short motif in the N-terminal region of α-synuclein is critical for both aggregation and function.

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