ATF4 Protects Against Neuronal Death in Cellular Parkinson's Disease Models by Maintaining Levels of Parkin

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder, for which there are no effective disease-modifying therapies. The transcription factor ATF4 is induced by multiple PD-relevant stressors, such as ER stress and oxidative damage. ATF4 may exert either protective or deleterious effects on cell survival, depending on the paradigm. However, the role of ATF4 in the pathogenesis of PD has not been explored. We find that ATF4 levels are increased in neuromelanin-positive neurons in the substantia nigra of a subset of Parkinson’s disease patients, relative to controls. ATF4 levels are also up-regulated in neuronal PC12 cells treated with the dopaminergic neuronal toxins toxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+). To explore the role of ATF4 in cell survival in PD-relevant contexts, we either silenced or overexpressed ATF4 in cellular models of PD. In neuronal PC12 cells, silencing of ATF4 enhanced cell death in response to either 6-OHDA or MPP+. Conversely, overexpression of ATF4 reduced cell death caused by dopaminergic neuronal toxins. ATF4 was also protective against 6-OHDA-induced death of cultured mouse ventral midbrain dopaminergic neurons. We further show that parkin, a gene associated with autosomal recessive PD, plays a critical role in ATF4-mediated protection. After treatment with 6-OHDA or MPP+, parkin protein levels fall, despite an increase in mRNA levels. ATF4 silencing exacerbates the toxin-induced reduction of parkin, while ATF4 overexpression partially preserves parkin levels. Finally, parkin silencing blocked the protective capacity of ATF4. These results indicate that ATF4 plays a protective role in Parkinson’s disease though the regulation of parkin.

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…Given the protective role of Parkin, these results suggest that ATF4 promotes dopaminergic cell survival during PD pathogenesis. Consistently, ATF4 levels are increased in neurons in the substantia nigra in a subset of PD patients compared with controls (Sun et al 2013). In addition, ATF4 overexpression in cellular models of PD reduces cell death, whereas silencing of ATF4 enhances cell death caused by 6-OHDA.…”

Midnolin is a novel regulator of parkin expression and is associated with Parkinson’s Disease

“…However, it is unclear whether ATF4 is beneficial or toxic in neuronal cells 17 . ATF4-null murine stroke-prone model systems displayed less neuronal loss than controls 25 , the ectopic expression of ATF4 increased the sensitivity of murine cortical neurons to ER stress-induced apoptosis, and neurons lacking ATF4 displayed markedly reduced cell death 26 .…”

STEP61is a substrate of the E3 ligase parkin and is upregulated in Parkinson’s disease

“…Moreover, PD toxins such as MPTP, rotenone, paraquat, and 6-hydroxydopamine alter parkin levels or its ligase activity and result in the accumulation of parkin substrates (31)(32)(33)(34)(35). Identification of new parkin substrates and characterization of their role or roles in synaptic function should result in a better understanding the molecular basis of PD.…”