The endoplasmic reticulum (ER) is an important organelle involved in protein quality control and cellular homeostasis. The accumulation of unfolded proteins leads to an ER stress, followed by an adaptive response via the activation of the unfolded protein response (UPR), PKR-like ER kinase (PERK), inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) and activating transcription factor 6 (ATF6) pathways. However, prolonged cell stress activates apoptosis signaling leading to cell death. Neuronal cells are particularly sensitive to protein misfolding, consequently ER and UPR dysfunctions were found to be involved in many neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and prions diseases, among others characterized by the accumulation and aggregation of misfolded proteins. Pharmacological UPR modulation in affected tissues may contribute to the treatment and prevention of neurodegeneration. The association between ER stress, UPR and neuropathology is well established. In this review, we provide up-to-date evidence of UPR activation in neurodegenerative disorders followed by therapeutic strategies targeting the UPR and ameliorating the toxic effects of protein unfolding and aggregation.

Metabolic disorders have become among the most serious threats to human health, leading to severe chronic diseases such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease, as well as cardiovascular diseases. Interestingly, despite the fact that each of these diseases has different physiological and clinical symptoms, they appear to share certain pathological traits such as intracellular stress and inflammation induced by metabolic disturbance stemmed from over nutrition frequently aggravated by a modern, sedentary life style. These modern ways of living inundate cells and organs with saturating levels of sugar and fat, leading to glycotoxicity and lipotoxicity that induce intracellular stress signaling ranging from oxidative to ER stress response to cope with the metabolic insults (Mukherjee, et al., 2015). In this review, we discuss the roles played by cellular stress and its responses in shaping metabolic disorders. We have summarized here current mechanistic insights explaining the pathogenesis of these disorders. These are followed by a discussion of the latest therapies targeting the stress response pathways.

Vitamin B12 (cobalamin) is a key determinant of S-adenosyl methionine (SAM)-dependent epigenomic cellular regulations related to methylation/acetylation and its deficiency produces neurodegenerative disorders by elusive mechanisms. Sirtuin 1 deacetylase (SIRT1) triggers cell response to nutritional stress through endoplasmic reticulum (ER) stress. Recently, we have established a N1E115 dopaminergic cell model by stable expression of a transcobalamin–oleosin chimera (TO), which impairs cellular availability of vitamin B12, decreases methionine synthase activity and SAM level, and reduces cell proliferation. In contrast, oleosin-transcobalamin chimera (OT) does not modify the phenotype of transfected cells. Presently, the impaired cellular availability of vitamin B12 in TO cells activated irreversible ER stress pathways, with increased P-eIF-2α, P-PERK, P-IRE1α, ATF6, ATF4, decreased chaperon proteins and increased pro-apoptotic markers, CHOP and cleaved caspase 3, through reduced SIRT1 expression and consequently greater acetylation of heat-shock factor protein 1 (HSF1). Adding either B12, SIRT1, or HSF1 activators as well as overexpressing SIRT1 or HSF1 dramatically reduced the activation of ER stress pathways in TO cells. Conversely, impairing SIRT1 and HSF1 by siRNA, expressing a dominant negative form of HSF1, or adding a SIRT1 inhibitor led to B12-dependent ER stress in OT cells. Addition of B12 abolished the activation of stress transducers and apoptosis, and increased the expression of protein chaperons in OT cells subjected to thapsigargin, a strong ER stress stimulator. AdoX, an inhibitor of methyltransferase activities, produced similar effects than decreased B12 availability on SIRT1 and ER stress by a mechanism related to increased expression of hypermethylated in cancer 1 (HIC1). Taken together, these data show that cellular vitamin B12 has a strong modulating influence on ER stress in N1E115 dopaminergic cells. The impaired cellular availability in vitamin B12 induces irreversible ER stress by greater acetylation of HSF1 through decreased SIRT1 expression, whereas adding vitamin B12 produces protective effects in cells subjected to ER stress stimulation.

The molecular mechanisms that underlie the neurological manifestations of patients with inherited diseases of vitamin B12 (cobalamin) metabolism remain to date obscure. We observed transcriptomic changes of genes involved in RNA metabolism and endoplasmic reticulum stress in a neuronal cell model with impaired cobalamin metabolism. These changes were related to the subcellular mislocalization of several RNA binding proteins, including the ELAVL1/HuR protein implicated in neuronal stress, in this cell model and in patient fibroblasts with inborn errors of cobalamin metabolism and Cd320 knockout mice. The decreased interaction of ELAVL1/HuR with the CRM1/exportin protein of the nuclear pore complex and its subsequent mislocalization resulted from hypomethylation at R-217 produced by decreased S-adenosylmethionine and protein methyl transferase CARM1 and dephosphorylation at S221 by increased protein phosphatase PP2A. The mislocalization of ELAVL1/HuR triggered the decreased expression of SIRT1 deacetylase and genes involved in brain development, neuroplasticity, myelin formation, and brain aging. The mislocalization was reversible upon treatment with siPpp2ca, cobalamin, S-adenosylmethionine, or PP2A inhibitor okadaic acid. In conclusion, our data highlight the key role of the disruption of ELAVL1/HuR nuclear export, with genomic changes consistent with the effects of inborn errors of Cbl metabolisms on brain development, neuroplasticity and myelin formation.