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

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.Peer reviewe

Unveiling the Function of the Mitochondrial Filament-Forming Protein LACTB in Lipid Metabolism and Cancer

LACTB is a relatively unknown mitochondrial protein structurally related to the bacterial penicillin-binding and beta-lactamase superfamily of serine proteases. LACTB has recently gained an increased interest due to its potential role in lipid metabolism and tumorigenesis. To date, around ninety studies pertaining to LACTB have been published, but the exact biochemical and cell biological function of LACTB still remain elusive. In this review, we summarise the current knowledge about LACTB with particular attention to the implications of the recently published study on the cryo-electron microscopy structure of the filamentous form of LACTB. From this and other studies, several specific properties of LACTB emerge, suggesting that the protein has distinct functions in different physiological settings. Resolving these issues by further research may ultimately lead to a unified model of LACTB’s function in cell and organismal physiology. LACTB is the only member of its protein family in higher animals and LACTB may, therefore, be of particular interest for future drug targeting initiatives

ER stress and UPR in Alzheimer's disease : mechanisms, pathogenesis, treatments

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by gradual loss of memory and cognitive function, which constitutes a heavy burden on the healthcare system globally. Current therapeutics to interfere with the underlying disease process in AD is still under development. Although many efforts have centered on the toxic forms of A beta to effectively tackle AD, considering the unsatisfactory results so far it is vital to examine other targets and therapeutic approaches as well. The endoplasmic reticulum (ER) stress refers to the build-up of unfolded or misfolded proteins within the ER, thus, perturbing the ER and cellular homeostasis. Emerging evidence indicates that ER stress contributes to the onset and development of AD. A thorough elucidation of ER stress machinery in AD pathology may help to open up new therapeutic avenues in the management of this devastating condition to relieve the cognitive dementia symptoms. Herein, we aim at deciphering the unique role of ER stress in AD pathogenesis, reviewing key findings, and existing controversy in an attempt to summarize plausible therapeutic interventions in the management of AD pathophysiology.Peer reviewe

Unveiling the Function of the Mitochondrial Filament-Forming Protein LACTB in Lipid Metabolism and Cancer

LACTB is a relatively unknown mitochondrial protein structurally related to the bacterial penicillin-binding and beta-lactamase superfamily of serine proteases. LACTB has recently gained an increased interest due to its potential role in lipid metabolism and tumorigenesis. To date, around ninety studies pertaining to LACTB have been published, but the exact biochemical and cell biological function of LACTB still remain elusive. In this review, we summarise the current knowledge about LACTB with particular attention to the implications of the recently published study on the cryo-electron microscopy structure of the filamentous form of LACTB. From this and other studies, several specific properties of LACTB emerge, suggesting that the protein has distinct functions in different physiological settings. Resolving these issues by further research may ultimately lead to a unified model of LACTB’s function in cell and organismal physiology. LACTB is the only member of its protein family in higher animals and LACTB may, therefore, be of particular interest for future drug targeting initiatives

Recent Insights into the Role of Unfolded Protein Response in ER Stress in Health and Disease

Peer reviewe

Lactate-Induced Glucose Output Is Unchanged by Metformin at a Therapeutic Concentration - A Mass Spectrometry Imaging Study of the Perfused Rat Liver

Metformin is the first line drug for type 2 diabetes but its molecular mechanisms remain unclear. Here, we have studied the acute effect of a therapeutically relevant intrahepatic concentration of metformin on glucose production from lactate. We selected the perfused rat liver as experimental system since it enables the complete control of drug dosage. We used MALDI (matrix-assisted laser desorption/ionization) mass spectrometry imaging to estimate the concentration of metformin in the livers and we measured the concentration of glucose in the effluent medium under basal conditions and following lactate addition. MALDI mass spectra of thin-sections of freeze-clamped rat liver perfused with metformin showed a peak at 130.16 m/z which was unambiguously assigned to metformin. The mass spectrometric detection limit was at a tissue concentration of about 250 nM, and uptake of metformin from the perfusion medium to the liver occurred with a K-m of 0.44 mM. Metformin was evenly distributed in the liver irrespective of its concentration in the perfusion medium and the duration of a perfusion. At a parenchymal concentration of 30 mu M, metformin did not induce any significant suppression of the basal or lactate-induced glucose release from the liver. These results show that matrix-assisted laser desorption/ionization mass spectrometry imaging can be applied to estimate the tissue concentration and distribution of metformin in a therapeutically relevant micromolar concentration range. Our findings challenge the view that metformin causes an inhibition of glucose release from the liver by an acute inhibition of mitochondrial glycerol 3-phosphate dehydrogenase (EC 1.1.5.3).Peer reviewe

Recent Insights into the Role of Unfolded Protein Response in ER Stress in Health and Disease

Unfolded stress response (UPR) is a conserved cellular pathway involved in protein quality control to maintain homeostasis under different conditions and disease states characterized by cell stress. Although three general schemes of and genes induced by UPR are rather well-established, open questions remain including the precise role of UPR in human diseases and the interactions between different sensor systems during cell stress signaling. Particularly, the issue how the normally adaptive and pro-survival UPR pathway turns into a deleterious process causing sustained endoplasmic reticulum (ER) stress and cell death requires more studies. UPR is also named a friend with multiple personalities that we need to understand better to fully recognize its role in normal physiology and in disease pathology. UPR interacts with other organelles including mitochondria, and with cell stress signals and degradation pathways such as autophagy and the ubiquitin proteasome system. Here we review current concepts and mechanisms of UPR as studied in different cells and model systems and highlight the relevance of UPR and related stress signals in various human diseases