The neuroprotective transcription factor ATF5 is decreased and sequestered into polyglutamine inclusions in Huntington’s disease

Abstract

Activating transcription factor-5 (ATF5) is a stress-response transcription factor induced upon different cell stressors like fasting, amino-acid limitation, cadmium or arsenite. ATF5 is also induced, and promotes transcription of anti-apoptotic target genes like MCL1, during the unfolded protein response (UPR) triggered by endoplasmic reticulum stress. In the brain, high ATF5 levels are found in gliomas and also in neural progenitor cells, which need to decrease their ATF5 levels for differentiation into mature neurons or glia. This initially led to believe that ATF5 is not expressed in adult neurons. More recently, we reported basal neuronal ATF5 expression in adult mouse brain and its neuroprotective induction during UPR in a mouse model of status epilepticus. Here we aimed to explore whether ATF5 is also expressed by neurons in human brain both in basal conditions and in Huntington's disease (HD), where UPR has been described to be partially impaired due to defective ATF6 processing. Apart from confirming that ATF5 is present in human adult neurons, here we report accumulation of ATF5 within the characteristic polyglutamine-containing neuronal nuclear inclusions in brains of HD patients and mice. This correlates with decreased levels of soluble ATF5 and of its antiapoptotic target MCL1. We then confirmed the deleterious effect of ATF5 deficiency in a Caenorhabditis elegans model of polyglutamine-induced toxicity. Finally, ATF5 overexpression attenuated polyglutamine-induced apoptosis in a cell model of HD. These results reflect that decreased ATF5 in HD-probably secondary to sequestration into inclusions-renders neurons more vulnerable to mutant huntingtin-induced apoptosis and that ATF5-increasing interventions might have therapeutic potential for HD.

Evaluation of Graphene Oxide Induced Cellular Toxicity and Transcriptome Analysis in Human Embryonic Kidney Cells

“…Previously, the expression of HSPA1A , a gene in the “negative regulation of inclusion body assembly” GO term (Figure 9), was shown to be enhanced in response to 6-hydroxy-2,2′,4,4′-tetrabromodiphenyl ether (6-OH-BDE-47) exposure [68]. Moreover, improper formation and accumulation of inclusion bodies were reported to elicit harmful effects on cell function and viability [69]. Phukan et al [70] demonstrated that exposing HEK293 cells to silica-coated magnetic nanoparticles aggravated proteasome function by reducing the expression of its regulators such as PSMA1, PSMA7, and PSME1 and increasing inclusion body assembly in the cytoplasm.…”

Protein Misfolding and ER Stress in Huntington's Disease

“…The inhibition of ERAD leads to accumulation of unfolded proteins in the ER, ER stress, and UPR induction, which were observed in HD models in yeast and mammalian cells (Duennwald and Lindquist, 2008; Reijonen et al, 2008; Carnemolla et al, 2009; Leitman et al, 2013, 2014), in animal HD models (Carnemolla et al, 2009; Cho et al, 2009; Noh et al, 2009; Vidal et al, 2012), and in post-mortem samples from HD patients (Carnemolla et al, 2009). Other cellular factors, such as ubiquitin-specific protease-14 and ATF5, are important for reduction of ER stress, and were recently found to be sequestered and depleted during mHtt aggregation (Hyrskyluoto et al, 2014; Hernández et al, 2017). One of the consequences of ER stress is to affect mitochondrial function and exacerbate oxidative stress, a key element in mHtt cytotoxicity (reviewed in Zheng et al, 2018).…”

Endogenous Mechanisms of Neuroprotection: To Boost or Not to Be

“…However, the subsequent consequences of these effects are not as clear. ATF5 induces the expression of two anti-apoptotic effectors (see below), B-cell lymphoma 2 (Bcl-2) and induced myeloid leukemia cell differentiation protein (Mcl-1) [103], which will inhibit apoptosis. ATF5 also modulates the mechanistic target of rapamycin (mTOR) in non-neuronal tissues, which is the main modulator of autophagy, interrelating UPR and autophagy.…”