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

Autori
Isabel Paiva ; Gaurav Jain ; Diana F. Lázaro ; Gotovac Jerčić, Kristina ; Thomas Hentrich ; Cemil Kerimoglu ; Raquel Pinho ; Èva M. Szegő ; Susanne Burkhardt ; Vincenzo Capece ; Rashi Halder ; Rezaul Islam ; Mary Xylaki ; Lucas A. Caldi Gomes ; Anna Elisa Roser ; Paul Lingor ; Julia M. Schulze-Hentrich ; Borovečki, Fran ; André Fischer ; Tiago F. Outeiro

Izvornik
Neurobiology of disease (0969-9961) 119 (2018); 121-135

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
A30P alpha-synuclein ; COL4A2 ; ER stress ; Golgi fragmentation ; Transcription deregulation

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kliničke medicinske znanosti

POVEZANOST RADA