Lactate metabolism in neurodegenerative diseases

Lactate,a byproduct of glycolysis,was thought to be a metabolic waste until the discovery of the Warburg effect.Lactate not only functions as a metabolic substrate to provide energy but can also function as a signaling molecule to modulate cellular functions under pathophysiological conditions.The Astrocyte-Neuron Lactate Shuttle has cla rified that lactate plays a pivotal role in the central nervous system.Moreover,protein lactylation highlights the novel role of lactate in regulating transcription,cellular functions,and disease development.This review summarizes the recent advances in lactate metabolism and its role in neurodegenerative diseases,thus providing optimal pers pectives for future research.

Mitochondrial calcium uniporter protein MCU is involved in oxidative stress-induced cell death

Mitochondrial calcium uniporter （MCU） is a conserved Ca2＋ transporter at mitochondrial in eukaryotic cells. However, the role of MCU protein in oxidative stress- induced cell death remains unclear. Here, we showed that ectopically expressed MCU is mitochondrial local- ized in both HeLa and primary cerebellar granule neu- rons （CGNs）. Knockdown of endogenous MCU decreases mitochondrial Ca2＋ uptake following his- tamine stimulation and attenuates cell death induced by oxidative stress in both HeLa cells and CGNs. We also found MCU interacts with VDACl and mediates VDAC1 overexpression-induced cell death in CGNs. This finding demonstrates that MCU-VDACl complex regulates mi- tochondrial Ca2＋ uptake and oxidative stress-induced apoptosis, which might represent therapeutic targets for oxidative stress related diseases.

Astrocytes in depression and Alzheimer’s disease

Astrocytes are an abundant subgroup of cells in the central nervous system(CNS)that play a critical role in controlling neuronal circuits involved in emotion,learning,and memory.In clinical cases,multiple chronic brain diseases may cause psychosocial and cognitive impairment,such as depression and Alzheimer’s disease(AD).For years,complex pathological conditions driven by depression and AD have been widely perceived to contribute to a high risk of disability,resulting in gradual loss of self-care ability,lower life qualities,and vast burden on human society.Interestingly,correlational research on depression and AD has shown that depression might be a prodrome of progressive degenerative neurological disease.As a kind of multifunctional glial cell in the CNS,astrocytes maintain physiological function via supporting neuronal cells,modulating pathologic niche,and regulating energy metabolism.Mounting evidence has shown that astrocytic dysfunction is involved in the progression of depression and AD.We herein review the current findings on the roles and mechanisms of astrocytes in the development of depression and AD,with an implication of potential therapeutic avenue for these diseases by targeting astrocytes.

Dlg1 Knockout Inhibits Microglial Activation and Alleviates Lipopolysaccharide-Induced Depression-Like Behavior in Mice

Microglia-mediated neuroinflammation is widely perceived as a contributor to numerous neurological diseases and mental disorders including depression.Discs large homolog 1(Dlg1),an adaptor protein,regulates cell polarization and the function of K?channels,which are reported to regulate the activation of microglia.However,little is known about the role of Dlg1 in microglia and the maintenance of central nervous system homeostasis.In this study,we found that Dlg1 knockdown suppressed lipopolysaccharide(LPS)-induced inflammation by downregulating the activation of nuclear factor-jB signaling and the mitogen-activated protein kinase pathway in microglia.Moreover,using an inducible Dlg1 microglia-specific knockout(Dlg1flox/flox;CX3CR1CreER)mouse line,we found that microglial Dlg1 knockout reduced the activation of microglia and alleviated the LPS-induced depressionlike behavior.In summary,our results demonstrated that Dlg1 plays a critical role in microglial activation and thus provides a potential therapeutic target for the clinical treatment of depression.

Redemystifying MST1/hippo signaling

Since the Mammalian Ste20-like kinases(MST)1/2 were first indentified in 1995,our knowledge about MST1/2 and its Drosophila ortholog Hippo has expanded to diverse biologic process ranging from cell survival and death,organ size control,to proliferation and tumorigenesis.MST1(also known as Stk4 and Krs2)and MST2(also known as Stk3 and Krs1)were first identified as homologs of the ste20 kinase from Saccharomyces cerevisiae(Creasy and Chernoff,1995).Subsequently,these proteins were also identified in‘in gel’kinase assays as kinases that respond to extreme cellular stress(Taylor et al.,1996).Though a number of apoptotic or stress stimuli have been reported to activate MST,proteolytic cleavage of MST by caspase 3 remains the only and best understood mechanism that regulate MST kinase activity to date(Kakeya et al.,1998).Upon proapoptotic stimuli,the N-terminal proteolytic fragment of MST translocates into the nucleus and phosphorylates histone H2B,which leads to the chromatin condensation and mammalian cell death(Cheung et al.,2003).Interestingly,histone H2B phosphorylation also occurs in S.cerevisiae,through the phosphorylation on Ser10,a residue distinct from mammalian histone H2B Ser14(Ahn et al.,2005).However,growing evidence suggests that full length MST also promotes cell death independently of proteolysis or nuclear translocation(Ahn et al.,2005;Lehtinen et al.,2006).In primary mammalian neurons,oxidative stress-activated-MST phosphorylates the transcription factor FOXO,which could translocate into the nucleus and upregulate the transcriptional activity of pro-death genes,including BIM.Moreover,the characterization of the C.elegans ortholog CST-1 broadens MST functions beyond the control of cell death to the regulation of life span in nematodes(Lehtinen et al.,2006).Despite the flurry of interest in the MST,both the upstream regulators and downstream targets of MST in different scenarios are still in a puzzle.

Generation of Calhm1 knockout mouse and characterization of calhm1 gene expression

Alzheimer’s disease(AD)is the most common neurode-generative disease among elderly people worldwide.Several genes have been validated to be associated with AD,and calcium homeostasis modulator 1(Calhm1)is the latest suspected one.To investigate the biological and pathological function of Calhm1 systematically,we generated a Calhm1 conventional knockout mouse.However,both the male and female of elderly Calhm1 knockout(KO)mice showed similar ability to their wild type littermates in spatial learning and memory retrieving.Surprisingly,we found that Calhm1 mRNA could not be detected in mouse brains at different ages,although it is expressed in the human brain tissues.We further found that CpG islands(CGIs)of both mouse and human Calhm1 were hypermethylated,whereas CGI of mouse Calhm2 was hypomethylated.In addition,transcriptional active marker H3K4Di occupied on promoters of human Calhm1 and mouse Calhm2 at a considerable level in brain tissues,while the occupancy of H3K4Di on pro-moter of mouse Calhm1 was rare.In sum,we found that mouse Calhm1 was of rare abundance in brain tissues.So it might not be suitable to utilize the knockout murine model to explore biological function of Calhm1 in the pathogenesis of AD.