Dataset Information

The loss of inhibitory C-terminal conformations in disease associated P123H ?-synuclein.

ABSTRACT: ?-synuclein (?S) is a homologue of ?-synuclein (?S), the major protein component of Lewy bodies in patients with Parkinson's disease. In contrast to ?S, ?S does not form fibrils, mitigates ?S toxicity in vivo and inhibits ?S fibril formation in vitro. Previously a missense mutation of ?S, P123H, was identified in patients with Dementia with Lewy Body disease. The single P123H mutation at the C-terminus of ?S is able to convert ?S from a nontoxic to a toxic protein that is also able to accelerate formation of inclusions when it is in the presence of ?S in vivo. To elucidate the molecular mechanisms of these processes, we compare the conformational properties of the monomer forms of ?S, ?S and P123H-?S, and the effects on fibril formation of coincubation of ?S with ?S, and with P123H-?S. NMR residual dipolar couplings and secondary structure propensities show that the P123H mutation of ?S renders it more flexible C-terminal to the mutation site and more ?S-like. In vitro Thioflavin T fluorescence experiments show that P123H-?S accelerates ?S fibril formation upon coincubation, as opposed to wild type ?S that acts as an inhibitor of ?S aggregation. When P123H-?S becomes more ?S-like it is unable to perform the protective function of ?S, which suggests that the extended polyproline II motif of ?S in the C-terminus is critical to its nontoxic nature and to inhibition of ?S upon coincubation. These studies may provide a basis for understanding which regions to target for therapeutic intervention in Parkinson's disease.

SUBMITTER: Janowska MK

PROVIDER: S-EPMC4815300 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Publications

The loss of inhibitory C-terminal conformations in disease associated P123H β-synuclein.

Janowska Maria K MK Baum Jean J

Protein science : a publication of the Protein Society 20150921 1

β-synuclein (βS) is a homologue of α-synuclein (αS), the major protein component of Lewy bodies in patients with Parkinson's disease. In contrast to αS, βS does not form fibrils, mitigates αS toxicity in vivo and inhibits αS fibril formation in vitro. Previously a missense mutation of βS, P123H, was identified in patients with Dementia with Lewy Body disease. The single P123H mutation at the C-terminus of βS is able to convert βS from a nontoxic to a toxic protein that is also able to accelerate ...[more]

PMID: 26332674

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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

The loss of inhibitory C-terminal conformations in disease associated P123H ?-synuclein.

Publications

The loss of inhibitory C-terminal conformations in disease associated P123H β-synuclein.

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