4E-BP1 Protects Neurons from Misfolded Protein Stress and Parkinson's Disease Toxicity by Inducing the Mitochondrial Unfolded Protein Response

Abstract

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. Overexpression of 4E-BP1 mediates the benefits of dietary restriction and can counter metabolic stress, and 4E-BP1 disinhibition on mTORC1 repression may be neuroprotective; however, whether 4E-BP1 overexpression is neuroprotective in mammalian neurons is yet to be fully explored. To address this question, we generated 4E-BP1-overexpressing transgenic mice and confirmed marked reductions in protein translation in 4E-BP1-overexpressing primary neurons. After documenting that 4E-BP1-overexpressing 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 upregulation of genes encoding proteins that comprise the mitochondrial unfolded protein response, and noted 4E-BP1 overexpression required activation of the mitochondrial unfolded protein response for neuroprotection against rotenone toxicity. We also tested whether 4E-BP1 could prevent a-synuclein neurotoxicity by treating 4E-BP1overexpressing primary neurons with a-synuclein preformed fibrils, and we observed marked reductions in a-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.

Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination

“…To our knowledge, the consequences of overexpression of these proteins in SCs has not been explored. However, overexpression of 4E-BP1 is neuroprotective in neuronal cultures treated with brefeldin A, rotenone, maneb, or paraquat ( Dastidar et al, 2020 ), compounds known to affect mitochondrial function ( Drechsel and Patel, 2008 ). Importantly, these neuroprotective effects are believed to be mediated by activation of the mtUPR downstream of 4E-BP1 ( Dastidar et al, 2020 ).…”

“…However, overexpression of 4E-BP1 is neuroprotective in neuronal cultures treated with brefeldin A, rotenone, maneb, or paraquat ( Dastidar et al, 2020 ), compounds known to affect mitochondrial function ( Drechsel and Patel, 2008 ). Importantly, these neuroprotective effects are believed to be mediated by activation of the mtUPR downstream of 4E-BP1 ( Dastidar et al, 2020 ). Moreover, upregulation of 4E-BP1 is protective in pancreatic islet cells in a context of ER stress in different models of diabetes ( Yamaguchi et al, 2008 ).…”

The Unfolded Protein Responses in Health, Aging, and Neurodegeneration: Recent Advances and Future Considerations

“…First, antibiotics that inhibit mitochondrial protein synthesis, namely doxycycline and chloramphenicol, have been shown to upregulate the expression of ATF5dependent UPR mt genes and extend lifespan in C. elegans (Houtkooper et al, 2013). Furthermore, repression of protein synthesis can also protect against Aβ and α-syn aggregation and neurotoxicity by inducing the expression of UPR mt -linked genes (Sorrentino et al, 2017;Dastidar et al, 2020). Second, drugs that increase the concentration of NAD + , or mimic this effect, appear to activate the ATF5-UPR mt and SIRT3-UPR mt to extend lifespan and protect against NDD-related cellular and organismal decline in various model systems (Belenky et al, 2007;Houtkooper et al, 2013;Mouchiroud et al, 2013;Regitz et al, 2016;Lehmann et al, 2017;Sorrentino et al, 2017).…”

Activation of the Mitochondrial Unfolded Protein Response: A New Therapeutic Target?

“…Mitochondrial diseases [60,64,73] Parkinson's disease [93][94][95][96]148] Alzheimer's disease [105][106][107][108][109] Huntington's disease [115] Amyotrophic lateral sclerosis [121][122][123][124] Heart diseases [132] Aging [139][140][141][142] Cancer [157,160] Author Contributions:…”

“…Ginseng protein protected against neurodegeneration by inducing UPR mt in a PINK1 fly model of PD [ 94 ]. Dastidar SG et al demonstrated that activation of 4E-BP1 correlates with UPR mt induction, which reduces PD associated neurotoxicity in mouse neurons [ 95 ]. In fact, mutant LRRK2 G2019S , the most common PD-causing allele in humans, results in reduced 4E-BP1 function and may contribute to PD pathogenesis by UPR mt underactivation [ 96 ].…”