Adaptive preconditioning in neurological diseases - therapeutic insights from proteostatic perturbations

Abstract

In neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a 'proteostasis network' and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge - the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson׳s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses and the molecular pathways they recruit might be exploited for therapeutic gain. This article is part of a Special Issue entitled SI:ER stress.

Keywords: Autophagy; ER stress; Glioblastoma; Hormesis; Ischemia; Parkinson׳s disease; Proteasome; Wolfram syndrome.

Fig. 1

The adaptive UPR in Parkinson׳s disease. In PD the UPR is activated. MPTP or 6-OHDA treatments induce ATF6 activation, oxidative stress and ubiquitin inclusions, which inhibit the proteasome. ATF6 confers neuroprotection to DA neurons by promoting ERAD factors that target misfolded protein to the proteasome and XBP1, which further alleviates ER stress by inducing expression of chaperones. ATF6 also induces the expression of BDNF, HO-1 and xCT that protects DA neurons. ATF6-mediated protection is hampered by α-synuclein which interacts with ATF6, inhibiting its activation by interfering with trafficking of COPII vesicles. The PERK/ATF4 branch is also activated and contributes to neuroprotection by inducing the expression of Parkin which in turn promotes mitophagy. α-synuclein also associates with PERK and may interfere with its function. IRE1/XBP1 contributes to neuroprotection by inducing BiP expression which limits overactivation of PERK and proapoptotic CHOP expression. BiP can also be induced via LRRK2 and the p38 pathway.

Fig. 2

The adaptive UPR in brain ischemia. In brain ischemia, excitotoxicity is induced by an excess of glutamate which overactivates NMDA receptors. This leads to rapid influx of Ca²⁺ into the cytoplasm. The increase of intracellular Ca²⁺ has several deleterious consequences including the activation of calpains that cleave many substrates leading to proteostatic disturbance, the loss of calcium homeostasis in the mitochondria followed by oxidative stress and ATP depletion, and inhibition of the SERCA pump at the ER with subsequent UPR activation. Ischemic preconditioning induces a wide range of protective responses favoring UPR adaptive arms (BiP, HERP), autophagy, the antioxidant response (SOD1, catalase) and proteasomal activity. Postconditioning also increases proteasome activity, which degrades Bim and increases Bcl-2 hence reducing apoptosis. These treatments awaken cellular adaptive mechanisms which, together with HIF1 responses, allow the cell to better resist stress and favor a fast return to normal proteostasis after injury. Moderate stimulation of the UPR activates its adaptive pathways, which is essential to restore protein homeostasis. PERK phosphorylates eIF2α and inhibits translation which is at first beneficial because it reduces the load of misfolded proteins. GCN2 also phosphorylates eIF2α and induces an adaptive program that is independent of this phosphorylation event. The dephosporylation of eIF2α by GADD34 restores protein synthesis. This is favored by eIF2β (induced by TLR activation) and allows expression of survival proteins and progressive resumption of proteostasis. IRE1 is a key adaptive response factor in ischemia; its specific modulation by interacting with Hsp72 or BI-1 promotes XBP1-dependent and independent responses to ensure cell survival while inhibiting JNK mediated cell death. Tg: thapsigargin.