J Neurosci. 2020 Oct 12. pii: JN-RM-0940-20. [Epub ahead of print]
Decline of protein quality control in neurons contributes to age-related neurodegenerative disorders caused by misfolded proteins. 4E-BP1 is a key node in the regulation of protein synthesis, as activated 4E-BP1 represses global protein translation. Over-expression of 4E-BP1 mediates the benefits of dietary restriction and can counter metabolic stress, and 4E-BP1 disinhibition upon mTORC1 repression may be neuroprotective; however, whether 4E-BP1 over-expression is neuroprotective in mammalian neurons is yet to be fully explored. To address this question, we generated 4E-BP1 over-expressing transgenic mice and confirmed marked reductions in protein translation in 4E-BP1 over-expressing primary neurons. After documenting that 4E-BP1 over-expressing neurons are resistant to proteotoxic stress elicited by brefeldin A treatment, we exposed primary neurons to three different Parkinson's disease (PD)-linked toxins, rotenone, maneb, or paraquat, and documented significant protection in neurons from newborn male and female 4E-BP1-OE transgenic mice. We observed 4E-BP1-dependent up-regulation of genes encoding proteins that comprise the mitochondrial unfolded protein response, and noted 4E-BP1 over-expression required activation of the mitochondrial unfolded protein response for neuroprotection against rotenone toxicity. We also tested if 4E-BP1 could prevent α-synuclein neurotoxicity by treating 4E-BP1 over-expressing primary neurons with α-synuclein preformed fibrils, and we observed marked reductions in α-synuclein aggregation and neurotoxicity, thus validating that 4E-BP1 is a powerful suppressor of PD-linked pathogenic insults. Our results indicate that increasing 4E-BP1 expression or enhancing 4E-BP1 activation can robustly induce the mitochondrial unfolded protein response and thus could be an appealing strategy for treating a variety of neurodegenerative diseases, including especially PD.Significance Statement:In neurodegenerative disease, misfolded proteins accumulate and overwhelm normal systems of homeostasis and quality control. One mechanism for improving protein quality control is to reduce protein translation. Here we investigated if neuronal over-expression of 4E-BP1, a key repressor of protein translation, can protect against misfolded protein stress and toxicities linked to Parkinson's disease, and found that 4E-BP1 over-expression prevented cell death in neurons treated with brefeldin A, rotenone, maneb, paraquat, or preformed fibrils of alpha-synuclein. When we sought the basis for 4E-BP1 neuroprotection, we discovered that 4E-BP1 activation promoted the mitochondrial unfolded protein response. Our findings highlight 4E-BP1 as a therapeutic target in neurodegenerative disease and underscore the importance of the mitochondrial unfolded protein response in neuroprotection against various insults.