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Heterogeneity in α-synuclein sub-types and their expression in cortical brain tissue lysates from Lewy body diseases and Alzheimer's disease

Lookup NU author(s): Dr Daniel Erskine, Dr Christopher Morris

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by Wiley, 2019.

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Abstract

Aims Lewy body diseases are neuropathologically characterized by the abnormal accumulation of α‐synuclein (α‐syn) protein within vulnerable neurons. Although studies have evaluated α‐syn in post‐mortem brain tissue, previous findings have been limited by typically employing pan‐α‐syn antibodies that may not recognize disease‐relevant forms of protein. We investigated the presence of α‐syn species present in post‐mortem brain tissues from Lewy body disease and Alzheimer's disease. Methods Soluble and insoluble/aggregated α‐syn from frontal cortex of post‐mortem brain tissues form Parkinson's disease (PD), dementia with Lewy bodies (DLB), Alzheimer's disease (AD) and aged control cases were sequentially extracted using buffers with increasing detergent concentrations. Enzyme‐linked immunosorbent assay (ELISA) was used to quantify the levels of total‐, oligomeric‐ and phosphorylated‐Ser129‐α‐syn (t‐, o‐ and pS129‐α‐syn). ELISA data were validated by western blot and compared to histological data from the same region of the contralateral hemisphere. Results There was no difference in t‐α‐syn levels between groups in the aqueous soluble, detergent soluble or urea soluble tissue fractions. However, aqueous soluble non‐phosphorylated o‐α‐syn was increased not only in PD and DLB, but also in AD without neocortical Lewy bodies. In PD and AD, pS129‐α‐syn was increased in the detergent soluble tissue fragment and, in AD, this was positively correlated with the burden of tau pathology. Increased levels of urea soluble pS129‐α‐syn were demonstrated only in DLB tissue lysates but this did not correlate with Lewy body pathological burden. Conclusions Taken together, these findings suggest that DLB have elevated levels of insoluble pS129‐α‐syn, but that increased levels of aqueous soluble o‐α‐syn and detergent soluble pS129‐α‐syn are also observed in PD and AD, suggesting different changes to α‐syn across the spectrum of neurodegenerative proteopathies.


Publication metadata

Author(s): Vaikath NN, Erskine D, Morris CM, Majbour N, Vekrellis K, Li JY, El-Agnaf OMA

Publication type: Article

Publication status: Published

Journal: Neuropathology and Applied Neurobiology

Year: 2019

Volume: 45

Issue: 6

Pages: 597-608

Print publication date: 01/10/2019

Online publication date: 13/11/2018

Acceptance date: 09/11/2018

Date deposited: 15/11/2018

ISSN (print): 0305-1846

ISSN (electronic): 1365-2990

Publisher: Wiley

URL: https://doi.org/10.1111/nan.12531

DOI: 10.1111/nan.12531

PubMed id: 30422353


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