The Unfolded Protein Response and Autophagy as Drug Targets in Neuropsychiatric Disorders

Abstract

Neurons are polarized in structure with a cytoplasmic compartment extending into dendrites and a long axon that terminates at the synapse. The high level of compartmentalization imposes specific challenges for protein quality control in neurons making them vulnerable to disturbances that may lead to neurological dysfunctions including neuropsychiatric diseases. Synapse and dendrites undergo structural modulations regulated by neuronal activity involve key proteins requiring strict control of their turnover rates and degradation pathways. Recent advances in the study of the unfolded protein response (UPR) and autophagy processes have brought novel insights into the specific roles of these processes in neuronal physiology and synaptic signaling. In this review, we highlight recent data and concepts about UPR and autophagy in neuropsychiatric disorders and synaptic plasticity including a brief outline of possible therapeutic approaches to influence UPR and autophagy signaling in these diseases.

Keywords: UPR; autophagy; drug; neuropsychiatric disease; synapse.

Figure 1

Involvement of unfolded protein response (UPR) in neuropsychiatric disorders. UPR is a major pathway in protein quality control in cells including neurons and is characterized by signaling cascades in the ER, mediated by the protein sensors, PERK, IRE1α, and activating transcription factor 6 (ATF6). Activation of PERK by autophosphorylation leads to phosphorylation of eukaryotic initiation factor 2 α (eIF2α), reducing the synthesis of critical synaptic proteins in neurons that affects memory processes and synaptic plasticity associated with intellectual disability, cognition, and addiction (Trinh et al., ; Placzek et al., 2016). PERK/eIF2α has also been linked to the pathophysiology of autism spectrum disorder (ASD) and mutant Neuroligin3 induced UPR and to anxiety-like behavior and GABAergic neuron damage in the amygdala (Ulbrich et al., ; Trobiani et al., 2018). IRE1α upon activation dimerizes and auto-phosphorylates which activates its kinase and RNase domain. The RNase domain further performs the unconventional splicing of XBP1 mRNA, resulting in spliced XBP1 mRNA that translates into a potent transcription factor, XBP1s (Uemura et al., 2009). XBP1 polymorphism in its promoter region has been associated with, Schizophrenia (SCZ), bipolar disorder (BD), and depression (Kakiuchi et al., ; Watanabe et al., ; Grunebaum et al., 2009). XBP1s also upregulates brain-derived neurotrophic factor (BDNF) that is a major factor involved in synaptic plasticity in health and disease. Activation of Protein kinase A (PKA) via cyclic AMP by different agents in the brain can in turn influence IRE1α (Saito et al., 2018). Inhibition of IRE1α ameliorated the social behavior deficits, a commonly observed trait in some neuropsychiatric disorders (Crider et al., 2018). Upon UPR induction, ATF6 is translocated to the Golgi apparatus for further processing by Site-1 and Site-2 proteases (S1P and S2P, respectively), leading to the release of amino-terminal fragment ATF6f with transcription factor functions. The expression of a mutant CASPR2 associated with ASD was shown to increase ATF6 (Falivelli et al., ; Canali et al., 2018). The precise role of ATF6 signaling in neuropsychiatric disorders warrants further investigations.

Figure 2

Aberrant autophagy processes in neuropsychiatric disorders. Mammalian target of rapamycin (mTOR) is a vital checkpoint in autophagy regulation. Hyperactive mTOR associated autophagy inhibition in Tuberous Sclerosis Complex 2 (Tsc2) and fragile X mental retardation protein (FMRP) deficient models result in ASD and Fragile X syndrome (FXS) pathologies, respectively (Tang et al., ; Yan et al., 2018). On the other hand, loss of TRIM32 leads to hypoactive mTOR and increased autophagy leading to ASD like pathology and loss of GABAergic interneurons (Zhu et al., 2019). Ulk2 deficiency causes autophagy inhibition and behavioral defects in rodents. Furthermore, hyperactive mTOR and Ulk2 deficiency mediated autophagy defects disrupt the gamma-aminobutyric acid (GABA) Type A Receptor-Associated Protein (GABARAP) mediated trafficking of GABA_A receptors to the plasma membrane (dashed line arrow; Sumitomo et al., ; Hui et al., 2019). An autophagy adapter protein, p62 sequesters GABARAP, and GABA_A receptors when autophagy is compromised. Also, communication between neurons and microglia is pivotal in maintaining healthy synapses. Microglia specific loss of autophagy results in ASD like behavioral deficits and reduced synaptic pruning whilst, microglia-mediated increase in synaptic pruning might be associated with the pathology of schizophrenia (SCZ; Sellgren et al., 2019). Direct involvement of microglia autophagy and synapse pruning in SCZ requires further studies.