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.

Sphingolipids as Modulators of SARS-CoV-2 Infection

“…Antidepressant, and antipsychotic drugs have different mechanisms of actions, including effects on cell stress responses and autophagy (Srinivasan et al, 2020). As shown previously, antidepressants influence autophagy via ceramide (Gulbins et al, 2018) but also other mechanisms that may be relevant for our understanding of SARS-CoV-2 pathogenesis and therapy.…”

Single Cell Atlas of Human Putamen Reveals Disease Specific Changes in Synucleinopathies: Parkinson’s Disease and Multiple System Atrophy

“…Recent single cell studies have put microglia into spotlight for neurodegenerative disease by showing the presence of a diseaseassociated population that could be playing a major role in neuroinflammation leading to a rapid synapse dysfunction [14]. UPR has been shown to play vital role in maintaining synaptic architecture and neuronal signaling [25]. Contrary to PD, absence of upregulated unfolded protein response in MSA microglia, accompanied with neuroinflammation may help explain rapid loss of synapse in MSA.…”

Inflammatory signaling mechanisms in bipolar disorder

“…SIGMAR-1 appears to have a wide range of protein interactions, also mediating inflammatory signaling in microglia and astrocytes across various neuropsychiatric disease models [ 65 ]. It has been shown to counteract apoptotic/inflammatory signals (via inositol 1, 4, 5-trisphosphate receptor (IP3R), Bcl-2 and NFkB regulation) and enhance neuroplasticity (via BDNF expression) [ 41 , 44 , 62 , 66 – 69 ]. It also acts as a key molecular chaperone in the unfolded protein response (UPR) system, which counteracts ER stress signals (ROS and hormonal).…”

“…They also appear as a common feature amongst psychotic, addictive, affective, and neurodegenerative conditions [ 69 ], possibly accounting for some of the phenotypic overlap across diagnoses. Several compounds with neuropsychiatric efficacy (lithium, valproic acid (VPA), haloperidol, fluvoxamine, fluoxetine, escitalopram, donepezil, ifenproil, and dehydroepiandosterone (DHEA)) appear to exert some of their positive effects via MAM/UPR pathways [ 67 , 69 – 71 ]. Moreover, both lithium and VPA potently enhance antiapoptotic Bcl-2 expression [ 72 ].…”