NeuralCipher Research overview
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Several studies have shown that Parkinson's disease causative gene products, including α-synuclein (α-syn), display tight links with the tumor suppressor p53. The purpose of this study is to determine the implication of α-syn in glioblastoma development and elucidate how it elicits a tumor suppressor function. We show that the expression of α-syn, a TP53 transcriptional target and a key molecular player in Parkinson's disease, is detected in 1p/19q-codeleted and isocitrate dehydrogenase (IDH)-mutant oligodendroglioma and in IDH-wild-type glioblastoma, while reduced in glioblastoma biopsies, corroborating the link of α-syn expression with a better prognosis among all glioma patients. Accordingly, protein expression is drastically reduced in oligodendrogliomas and glioblastoma biopsies. This could be accounted for by a reduction of p53 transcriptional activity in these samples. Interestingly, genetic manipulation of p53 in glioblastoma cells and in mouse brain shows that p53 up-regulates α-synuclein, a phenotype fully abolished by the prominent p53 hot spot mutation R175H. Downstream to its p53-linked control, α-syn lowers cyclin D1 protein and mRNA levels and reduces glioblastoma cells proliferation in a cyclin D1-dependent-manner. Further, in temozolomide (TMZ)-resistant U87 cells, α-syn reduces O6-methylguanine-DNA methyltransferase (MGMT) expression and rescues drug sensitivity by a mechanism implying its transcriptional activation by X-box binding protein 1 (XBP1), an effector of the UPR response. Furthermore, α-syn lowers MGMT and cyclin D1 (CCDN1) expressions and reduces tumor development in allografted mice. Overall, our data reveals a new role of α-syn as an oligodendroglioma biomarker and as a glioblastoma tumor suppressor capable of either potentiate TMZ effect or avoid TMZ-associated resistance.
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