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Mutation of Tyrosine Sites in the Human Alpha-Synuclein Gene Induces Neurotoxicity in Transgenic Mice with Soluble Alpha-Synuclein Oligomer Formation

Lookup NU author(s): Professor Tiago OuteiroORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2022 by the authors.Overexpression of α-synuclein with tyrosine mutated to phenylalanine at position 125 leads to a severe phenotype with motor impairment and neuropathology in Drosophila. Here, we hypothesized that tyrosine mutations would similarly lead to impaired motor performance with neuropathology in a rodent model. In transgenic mice (ASO), tyrosines at positions 125, 133, and 136 in human α-synuclein were mutated to phenylalanine and cloned into a Thy1.2 expression vector, which was used to create transgenic mouse lines on a mixed genetic background TgN(Thy-1-SNCA-YF)4Emfu (YF). The YF mice had a decreased lifespan and displayed a dramatic motor phenotype with paralysis of both hind- and forelegs. Post-translational modification of α-synuclein due to phosphorylation of serine 129 is often seen in inclusions in the brains of patients with α-synucleinopathies. We observed a slight but significant increase in phosphorylation of serine 129 in the cytosol in YF mice compared to age-matched human α-synuclein transgenic mice (ASO). Conversely, significantly decreased phosphorylation of serine 129 was seen in synaptosomes of YF mice that also contained higher amounts of soluble oligomers. YF mice deposited full-length α-synuclein aggregates in neurons widespread in the CNS with the main occurrence in the forebrain structures of the cerebral cortex, the basal ganglia, and limbic structures. Full-length α-synuclein labeling was also prominent in many nuclear regions of the brain stem, deep cerebellar nuclei, and cerebellar cortex. The study shows that the substitution of tyrosines to phenylalanine in α-synuclein at positions 125, 133, and 136 leads to severe toxicity in vivo. An insignificant change upon tyrosine substitution suggests that the phosphorylation of serine 129 is not the cause of the toxicity.

Publication metadata

Author(s): Lassen LB, Thomsen MS, Basso E, Fuchtbauer E-M, Fuchtbauer A, Outeiro TF, Jensen PH, Moos T

Publication type: Article

Publication status: Published

Journal: Cells

Year: 2022

Volume: 11

Issue: 22

Online publication date: 18/11/2022

Acceptance date: 13/11/2022

Date deposited: 05/12/2022

ISSN (electronic): 2073-4409

Publisher: MDPI

URL: https://doi.org/10.3390/cells11223673

DOI: 10.3390/cells11223673

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