Journal Article

DZNE-2020-06539

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Alpha-synuclein deregulates the expression of COL4A2 and impairs ER-Golgi function.

Paiva, I. ; Jain, G.DZNE* ; Lázaro, D. F. ; Jerčić, K. G. ; Hentrich, T. ; Kerimoglu, C.DZNE* ; Pinho, R. ; Szegő, È. M. ; Burkhardt, S.DZNE* ; Capece, V.DZNE* ; Halder, R.DZNE* ; Islam, R.DZNE* ; Xylaki, M. ; Caldi Gomes, L. A. ; Roser, A.-E. ; Lingor, P. ; Schulze-Hentrich, J. M. ; Borovečki, F. ; Fischer, A.DZNE* ; Outeiro, T. F. (Corresponding author)

2018
Academic Press Orlando, Fla.

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Please use a persistent id in citations: doi:10.1016/j.nbd.2018.08.001

Abstract: 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.

Keyword(s): Animals (MeSH) ; Cells, Cultured (MeSH) ; Collagen Type IV: biosynthesis (MeSH) ; Collagen Type IV: genetics (MeSH) ; Endoplasmic Reticulum: physiology (MeSH) ; Gene Expression (MeSH) ; Golgi Apparatus: physiology (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Mice, Inbred C57BL (MeSH) ; Mice, Transgenic (MeSH) ; Peptide Fragments: biosynthesis (MeSH) ; Peptide Fragments: genetics (MeSH) ; alpha-Synuclein: biosynthesis (MeSH) ; alpha-Synuclein: genetics (MeSH) ; Col4a2 protein, mouse ; Collagen Type IV ; Peptide Fragments ; Snca protein, mouse ; alpha-Synuclein

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Contributing Institute(s):

1. Epigenetics and Systems Medicine in Neurodegenerative Diseases (AG Fischer)
2. Computational Systems Biology (AG Bonn 2)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2018

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Database coverage:
; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DOAJ Seal ; Ebsco Academic Search ; IF >= 5 ; JCR ; SCOPUS ; Web of Science Core Collection

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