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.
journal_name
Neurobiol Disjournal_title
Neurobiology of diseaseauthors
Paiva I,Jain G,Lázaro DF,Jerčić KG,Hentrich T,Kerimoglu C,Pinho R,Szegő ÈM,Burkhardt S,Capece V,Halder R,Islam R,Xylaki M,Caldi Gomes LA,Roser AE,Lingor P,Schulze-Hentrich JM,Borovečki F,Fischer A,Outeiro TFdoi
10.1016/j.nbd.2018.08.001subject
Has Abstractpub_date
2018-11-01 00:00:00pages
121-135eissn
0969-9961issn
1095-953Xpii
S0969-9961(18)30392-9journal_volume
119pub_type
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