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Alpha-synuclein deregulates the expression of COL4A2 and impairs ER-Golgi function

Lookup NU author(s): Professor Tiago OuteiroORCiD

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Abstract

© 2018 Elsevier Inc. Alpha-synuclein (aSyn) is the major protein component of Lewy bodies and Lewy neurites, the typical pathological hallmarks in Parkinson's disease (PD) and Dementia with Lewy bodies. aSyn is capable of inducing transcriptional deregulation, but the precise effect of specific aSyn mutants associated with familial forms of PD, remains unclear. Here, we used transgenic mice overexpressing human wild-type (WT) or A30P aSyn to compare the transcriptional profiles of the two animal models. We found that A30P aSyn promotes strong transcriptional deregulation and increases DNA binding. Interestingly, COL4A2, a major component of basement membranes, was found to be upregulated in both A30P aSyn transgenic mice and in dopaminergic neurons expressing A30P aSyn, suggesting a crucial role for collagen related genes in aSyn-induced toxicity. Finally, we observed that A30P aSyn alters Golgi morphology and increases the susceptibility to endoplasmic reticulum (ER) stress in dopaminergic cells. In total, our findings provide novel insight into the putative role of aSyn on transcription and on the molecular mechanisms involved, thereby opening novel avenues for future therapeutic interventions in PD and other synucleinopathies.

Publication metadata

Author(s): Paiva I, Jain G, Lazaro DF, Jercic KG, Hentrich T, Kerimoglu C, Pinho R, Szego EM, Burkhardt S, Capece V, Halder R, Islam R, Xylaki M, Caldi Gomes LA, Roser A-E, Lingor P, Schulze-Hentrich JM, Borovecki F, Fischer A, Outeiro TF

Publication type: Article

Publication status: Published

Journal: Neurobiology of Disease

Year: 2018

Volume: 119

Pages: 121-135

Print publication date: 01/11/2018

Online publication date: 06/08/2018

Acceptance date: 03/08/2018

ISSN (print): 0969-9961

ISSN (electronic): 1095-953X

Publisher: Academic Press Inc.

URL: https://doi.org/10.1016/j.nbd.2018.08.001

DOI: 10.1016/j.nbd.2018.08.001

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