Protein synthesis modulation as a therapeutic approach for amyotrophic lateral sclerosis and frontotemporal dementia

Protein synthesis is essential for cells to perform life metabolic processes.Pathological alterations of protein content can lead to particular diseases.Cells have an intrinsic array of mechanisms and pathways that are activated when protein misfolding,accumulation,aggregation or mislocalization occur.Some of them(like the unfolded protein response)represent complex interactions between endoplasmic reticulum sensors and elongation factors that tend to increase expression of chaperone proteins and/or repress translation in order to restore protein homeostasis(also known as proteostasis).This is even more important in neurons,as they are very susceptible to harmful effects associated with protein overload and proteostatic mechanisms are less effective with age.Several neurodegenerative pathologies such as Alzheimer’s,Parkinson’s,and Huntington’s diseases,amyotrophic lateral sclerosis and frontotemporal dementia exhibit a particular molecular signature of distinct,unbalanced protein overload.In amyotrophic lateral sclerosis and frontotemporal dementia,the majority of cases present intracellular inclusions of ubiquitinated transactive response DNA-binding protein of 43 kDa(TDP-43).TDP-43 is an RNA binding protein that participates in RNA metabolism,among other functions.Dysregulation of TDP-43(e.g.aggregation and mislocalization)can dramatically affect neurons,and this has been linked to disease development.Expression of amyotrophic lateral sclerosis/frontotemporal dementia TDP-43-related mutations in cellular and animal models has been shown to recapitulate key features of the amyotrophic lateral sclerosis/frontotemporal dementia disease spectrum.These variants can be causative of degeneration onset and progression.Most neurodegenerative diseases(including amyotrophic lateral sclerosis and frontotemporal dementia)have no cure at the moment;however,modulating translation has recently emerged as an attractive approach that can be performed at several steps(i.e.regulating activation of initiation and elongation factors,inhibiting unfolded protein response activation or inducing chaperone expression and activity).This review focuses on the features of protein imbalance in neurodegenerative disorders and the relevance of developing therapeutical compounds aiming at restoring proteostasis.We strive to highlight the importance of research on drugs that,not only restore protein imbalance without compromising translational activity of cells,but are also as safe as possible for the patients.

Transactive Demand Response Operation at the Grid Edge using the IEEE 2030.5 Standard

This paper presents a transactive demand response(TDR)scheme for a network of residential customers with generation assets that emphasizes interoperability within a transactive energy architecture.A complete laboratory-based implementation provides the first(to our knowledge)realization of a comprehensive TDR use case that is fully compliant with the Institute of Electrical and Electronics Engineers(IEEE)2030.5 standard,which addresses interoperability within a cybersecure smart energy profile(SEP)context.Verification is provided by a full system integration with commercial hardware using Internet Protocol(IP)-based(local area network(LAN)and Wi-Fi)communication protocols and transport layer security(TLS)1.2 cryptographic protocol,and validation is provided by emulation using extensive residential smart meter data.The demand response(DR)scheme is designed to accommodate privacy concerns,allows customers to select their DR compliance level,and provides incentives to maximize their participation.The proposed TDR scheme addresses privacy through the implementation of the SEP 2.0 messaging protocol between a transactive agent(TA)and home energy management system(HEMS)agents.Customer response is handled by a multi-input multi-output(MIMO)fuzzy controller that manages negotiation between the customer agent and the TA.We take a multi-agent system approach to neighborhood coordination,with the TA servicing multiple residences on a common transformer,and use a reward mechanism to maximize customer engagement during the event-based optimization.Based on a set of smart meter data acquired over an extended time period,we engage in multiple TDR scenarios,and demonstrate with a fully-functional IEEE 2030.5-compliant implementation that our scheme can reduce network peak power consumption by 22%under realistic conditions.

Combined Treatment with Bojungikgi-tang(Buzhong Yiqi Decoction)and Riluzole Attenuates Cell Death in TDP-43-Expressing Cells

Objective To examine the effect of combined treatment with Bojungikgi-tang(BJIGT,Buzhong Yiqi Decoction)and riluzole(RZ)in transactive response DNA-binding protein 43(TDP-43)stress granule(SG)cells,a amyotrophic lateral sclerosis(ALS)cell line using transcriptomic and molecular techniques.Methods TDP-43 SG cells were pretreated with BJIGT(100µg/mL),RZ(50µmol/L),and combined BJIGT(100µg/mL)/RZ(50µmol/L)for 6 h before treatment with lipopolysaccharide(LPS,200µmol/L).Cell viability assay was performed to elucidate cell toxicity in TDP-43 SC cells using a cell-counting kit-8(CCK8)assay kit.The expression levels of cell death-related proteins,including Bax,caspase 1,cleaved caspase 3 and DJ1 in TDP-43 SG cells were examined by Western blot analysis.The autophagy-related proteins,including pmTOR/mTOR,LC3b,P62,ATG7 and Bcl-2-associated athanogene 3(Bag3)were investigated using immunofluorescence and immunoblotting assays.Results Cell viability assay and Western blot analysis showed that combined treatment with BJIGT and RZ suppressed LPS-induced cell death and expression of cell death-related proteins,including Bax,caspase 1,and DJ1(P<0.05 or P<0.01).Immunofluorescence and immunoblotting assays showed that combined treatment with BJIGT and RZ reduced LPS-induced formation of TDP-43 aggregates and regulated autophagy-related protein levels,including p62,light chain 3b,Bag3,and ATG7,in TDP-43-expressing cells(P<0.05 or P<0.01).Conclusion The combined treatment of BJIGT and RZ might reduce inflammation and regulate autophagy dysfunction in TDP-43-induced ALS.