Guanabenz promotes neuronal survival via enhancement of ATF4 and parkin expression in models of Parkinson disease.

Guanabenz promotes neuronal survival via enhancement of ATF4 and parkin expression in models of Parkinson disease. Exp Neurol. 2018 Feb 09;: Authors: Sun X, Aimé P, Dai D, Ramalingam N, Crary JF, Burke RE, Greene LA, Levy OA Abstract Reduced function of parkin appears to be a central pathogenic event in Parkinson disease (PD). Increasing parkin levels enhances survival in models of PD-related neuronal death and is a promising therapeutic objective. Previously, we demonstrated that the transcription factor ATF4 promotes survival in response to PD-mimetic stressors by maintaining parkin levels. ATF4 translation is up-regulated by phosphorylation of the translation initiation factor eIF2α. The small molecule guanabenz enhances eIF2α phosphorylation by blocking the function of GADD34, a regulatory protein that promotes eIF2α dephosphorylation. We tested the hypothesis that guanabenz, by inhibiting GADD34 and consequently increasing eIF2α phosphorylation and elevating ATF4, would improve survival in models of PD by up-regulating parkin. We found that GADD34 is strongly induced by 6-OHDA, and that GADD34 localization is dramatically altered in dopaminergic substantia nigra neurons in PD cases. We further demonstrated that guanabenz attenuates 6-hydroxydopamine (6-OHDA) induced cell death of differentiated PC12 cells and primary ventral midbrain dopaminergic neurons in culture, and of dopaminergic neurons in the substantia nigra of mic...
Source: Experimental Neurology - Category: Neurology Authors: Tags: Exp Neurol Source Type: research