Alpha-synuclein deregulates the expression of COL4A2 and impairs ER-Golgi function
| Autor: | Diana F. Lázaro, Cemil Kerimoglu, Fran Borovečki, Éva M. Szegő, Mary Xylaki, Isabel Paiva, Susanne Burkhardt, Vincenzo Capece, Rezaul Islam, Anna Elisa Roser, Raquel Pinho, Kristina Gotovac Jerčić, Lucas Caldi Gomes, Gaurav Jain, Thomas Hentrich, Rashi Halder, Andre Fischer, Tiago F. Outeiro, Paul Lingor, Julia M. Schulze-Hentrich |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
biosynthesis [Collagen Type IV] Golgi Apparatus Gene Expression Endoplasmic Reticulum chemistry.chemical_compound Mice 0302 clinical medicine genetics [Collagen Type IV] Cells Cultured physiology [Endoplasmic Reticulum] Snca protein mouse Cell biology Neurology Transcription deregulation symbols genetics [alpha-Synuclein] alpha-Synuclein ER stress Golgi fragmentation Genetically modified mouse Collagen Type IV biosynthesis [Peptide Fragments] Transgene COL4A2 Mice Transgenic Biology lcsh:RC321-571 03 medical and health sciences symbols.namesake ddc:570 medicine Animals Humans A30P alpha-synuclein biosynthesis [alpha-Synuclein] lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Alpha-synuclein Synucleinopathies Dementia with Lewy bodies physiology [Golgi Apparatus] Endoplasmic reticulum Golgi apparatus medicine.disease genetics [Peptide Fragments] Peptide Fragments Mice Inbred C57BL 030104 developmental biology chemistry Unfolded protein response Col4a2 protein mouse 030217 neurology & neurosurgery |
| Zdroj: | Neurobiology of disease 119, 121-135 (2018). doi:10.1016/j.nbd.2018.08.001 Neurobiology of Disease, Vol 119, Iss, Pp 121-135 (2018) |
| DOI: | 10.1016/j.nbd.2018.08.001 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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