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BBA - Molecular Basis of Disease (v.1792, #1)

Editorial Board (pp. ii).

Reviewer Acknowledgment (pp. 1-2).

Autophagy: Principles and significance in health and disease by Virginia Todde; Marten Veenhuis; Ida J. van der Klei ⁎ (pp. 3-13).

Degradation processes are important for optimal functioning of eukaryotic cells. The two major protein degradation pathways in eukaryotes are the ubiquitin–proteasome pathway and autophagy. This contribution focuses on autophagy. This process is important for survival of cells during nitrogen starvation conditions but also has a house keeping function in removing exhausted, redundant or unwanted cellular components. We present an overview of the molecular mechanism involved in three major autophagy pathways: chaperone mediated autophagy, microautophagy and macroautophagy. Various recent reports indicate that autophagy plays a crucial role in human health and disease. Examples are presented of lysosomal storage diseases and the role of autophagy in cancer, neurodegenerative diseases, defense against pathogens and cell death.

Keywords: Yeast; Autophagy; ATG; genes; Vacuole; Lysosome; Autophagosome

Alternative splicing and disease by Jamal Tazi; Nadia Bakkour; Stefan Stamm (pp. 14-26).

Almost all protein-coding genes are spliced and their majority is alternatively spliced. Alternative splicing is a key element in eukaryotic gene expression that increases the coding capacity of the human genome and an increasing number of examples illustrates that the selection of wrong splice sites causes human disease. A fine-tuned balance of factors regulates splice site selection. Here, we discuss well-studied examples that show how a disturbance of this balance can cause human disease. The rapidly emerging knowledge of splicing regulation now allows the development of treatment options.

Keywords: Alternative splicing; Disease; Splicing code; Mutation

Are MYO1C and MYO1F associated with hearing loss? by Cristina Zadro; Maria Stella Alemanno; Emanuele Bellacchio; Romina Ficarella; Francesca Donaudy; Salvatore Melchionda; Leopoldo Zelante; Raquel Rabionet; Nele Hilgert; Xavier Estivill; Guy Van Camp; Paolo Gasparini; Massimo Carella (pp. 27-32).

The role of myosins in the pathogenesis of hearing loss is well established: five genes encoding unconventional myosins and two genes encoding nonmuscle conventional myosins have so far been described to be essential for normal auditory function and mutations in these genes associated with hearing impairment. To better understand the role of this gene family we performed a mutational screening on two candidate genes, MYO1C and MYO1F, analyzing hundreds of patients, affected by bilateral sensorineural hearing loss and coming from different European countries. This research activity led to the identification of 6 heterozygous missense mutations in MYO1C and additional 5 heterozygous missense mutations in MYO1F. Homology modelling suggests that some of these mutations could have a potential influence on the structure of the ATP binding site and could probably affect the ATPase activity or the actin binding process of both myosins. This study suggests a role of the above mentioned myosin genes in the pathogenesis of hearing loss.

Keywords: Hearing loss; MYO1C; MYO1F

Menthol regulates TRPM8-independent processes in PC-3 prostate cancer cells by Su-Hwa Kim; Joo-Hyun Nam; Eun-Jung Park; Byung-Joo Kim; Sung-Joon Kim; Insuk So; Ju-Hong Jeon (pp. 33-38).

Menthol, a naturally occurring compound from peppermint oil, binds and activates the TRPM8 Ca²⁺-permeable channel that exhibits abnormal expression patterns in prostate cancer, suggesting that TRPM8 links Ca²⁺ transport pathways to tumor biology. We thus investigated the cellular responses of prostate cancer cells to menthol. Here we found that menthol increases [Ca²⁺]_i via Ca²⁺ influx mechanism(s) independent of TRPM8 in PC-3 cells. We demonstrated that menthol induces cell death at supramillimolar concentrations in PC-3 cells and the cell death is not suppressed by low extracellular Ca²⁺ condition which indicates that menthol-induced cell death is not associated with Ca²⁺ influx pathways. In addition, we showed that menthol increases a phosphorylated form of c-jun N-terminal kinase (JNK) in PC-3 cells through TRPM8-independent mechanisms. Thus, our data indicate that there is an apparent lack of causality between TRPM8 activation and menthol-induced cell death and that menthol can regulate TRPM8-independent Ca²⁺-transport and cellular processes.

Keywords: Abbreviations; TRPM8; transient receptor potential melastatin 8; I–V curve; current to voltage relation curve; JNK; c-jun N-terminal kinaseMenthol; TRPM8; Ca; ²⁺; Prostate cancer; Cell death

Niacin bound chromium treatment induces myocardial Glut-4 translocation and caveolar interaction via Akt, AMPK and eNOS phosphorylation in streptozotocin induced diabetic rats after ischemia-reperfusion injury by Suresh Varma Penumathsa; Mahesh Thirunavukkarasu; Samson Mathews Samuel; Lijun Zhan; Gautam Maulik; Manashi Bagchi; Debasis Bagchi; Nilanjana Maulik (pp. 39-48).

Diabetes, one of the major risk factors of metabolic syndrome culminates in the development of Ischemic Heart Disease (IHD). Refined diets that lack micronutrients, mainly trivalent chromium (Cr³⁺) have been identified as the contributor in the rising incidence of diabetes. We investigated the effect of niacin-bound chromium (NBC) during ischemia/reperfusion (IR) injury in streptozotocin induced diabetic rats. Rats were randomized into: Control (Con); Diabetic (Dia) and Diabetic rats fed with NBC (Dia+NBC). After 30 days of treatment, the isolated hearts were subjected to 30 min of global ischemia followed by 2 h of reperfusion. NBC treatment demonstrated significant increase in left ventricular functions and significant reduction in infarct size and cardiomyocyte apoptosis in Dia+NBC compared with Dia. Increased Glut-4 translocation to the lipid raft fractions was also observed in Dia+NBC compared to Dia. Reduced Cav-1 and increased Cav-3 expression along with phosphorylation of Akt, eNOS and AMPK might have resulted in increased Glut-4 translocation in Dia+NBC. Our results indicate that the cardioprotective effect of NBC is mediated by increased activation of AMPK, Akt and eNOS resulting in increased translocation of Glut-4 to the caveolar raft fractions thereby alleviating the effects of IR injury in the diabetic myocardium.

Keywords: Chromium; Diabetes; eNOS; Heart; Glut-4; Ischemia reperfusion

Methionine does not reduce Cu(II)–β-amyloid!—Rectification of the roles of methionine-35 and reducing agents in metal-centered oxidation chemistry of Cu(II)–β-amyloid by Giordano F.Z. da Silva; Vasiliky Lykourinou; Alexander Angerhofer ⁎; Li-June Ming ⁎ (pp. 49-55).

The potential risk of metal-centered oxidative catalysis has been overlooked in the research of the copper complexes of the Alzheimer's disease-related β-amyloid (Aβ) peptides. Cu²⁺ complexes of Aβ_1–40 and its 1–16 and 1–20 fragments have recently been shown to exhibit significant metal-centered oxidative activities toward several catecholamine neurotransmitters with and without H₂O₂ around neutral pH [G.F.Z. da Silva, L.-J. Ming, “Metallo-ROS” in Alzheimer's disease: metal-centered oxidation of neurotransmitters by Cu^II–β-amyloid and neuropathology of Alzheimer's disease, Angew. Chem. Int. Ed. 46 (2007) 3337–3341]. The results further support the metallo-Aβ-associated oxidative stress theory often considered to be connected to the neuropathology of the disease. The metal-centered oxidative catalysis of CuAβ_1–16/20 challenges the long-standing proposed redox role of Met35 in Aβ because Aβ_1–16/20 do not contain a Met. External Met has been determined by kinetic, optical, and electron paramagnetic resonance methods to bind directly to the Cu²⁺ center of CuAβ_1–40 and CuAβ_1–20 with K_d=2.8 mM and 11.3 μM, respectively, which reflects less accessibility of the metal center in the full-length CuAβ_1–40. However, Met does not serve as a reducing agent for the Cu(II) which thus must amplify the observed oxidative catalysis of CuAβ_1–20 through a non-redox mechanism. Conversely, the CuAβ-catalyzed oxidation reaction of dopamine is inhibited by bio-available reducing agents such as ascorbate (competitive K_ic=66 μM) and glutathione (non-competitive, K_inc=53 μM). These data indicate that the oxidation chemistry of metallo-Aβ is not initiated by Met35. The results yield further molecular and mechanistic insights into the roles of metallo-Aβ in this disease.

Keywords: Abbreviations; Aβ; β-amyloid peptide; AD; Alzheimer's diseases; APP; amyloid precursor protein; EPR; electronparamagnetic resonance; ESEEM; electron spin echo envelope modulation; GSH; glutathione; HEPES; 4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid; MBTH; 3-methyl-2-benzothiazolinone hydrazone hydrochloride monohydrate; NMR; nuclear magnetic resonance; NQI; nuclear quadrupole interaction; ROS; reactive oxygen speciesAlzheimer's disease; β-amyloid; Ascorbic acid; Catechol oxidase; Copper; Methionine; Reducing agent

Protection of cerulein-induced pancreatic fibrosis by pancreas-specific expression of Smad7 by Jing He; Xiaolan Sun; Ke-Qing Qian; Xubao Liu; Zhenzhen Wang; Yan Chen ⁎ (pp. 56-60).

Pancreatic fibrosis is the hallmark of chronic pancreatitis, currently an incurable disease. Pancreatitis fibrosis is caused by deposition of extracellular matrix (ECM) and the underlying pathological mechanism remains unclear. In addition to its broad biological activities, TGF-β is a potent pro-fibrotic factor and many in vitro studies using cell systems have implicated a functional role of TGF-β in the pathogenesis of pancreatic fibrosis. We analyzed the in vivo role of TGF-β pathway in pancreatic fibrosis in this study. Smad7, an intracellular inhibitory protein that antagonizes TGF-β signaling, was specifically expressed in the pancreas using a transgenic mouse model. Chronic pancreatitis was induced in the mouse with repeated administration of cerulein. Smad7 expression in the pancreas was able to significantly inhibit cerulein-induced pancreatic fibrosis. Consistently, the protein levels of collagen I and fibronectin were decreased in the Smad7 transgenic mice. In addition, α-smooth muscle actin, a marker of activated pancreas stellate cells, was reduced in the transgenic mice. Taken together, these data indicate that inhibition of TGF-β signaling by Smad7 is able to protect cerulein-induced pancreatic fibrosis in vivo.

Keywords: Chronic pancreatitis; Fibrosis; Smad7; TGF-β; Transgenic mouse

GALNT3, a gene associated with hyperphosphatemic familial tumoral calcinosis, is transcriptionally regulated by extracellular phosphate and modulates matrix metalloproteinase activity by Ilana Chefetz; Kimitoshi Kohno; Hiroto Izumi; Jouni Uitto; Gabriele Richard; Eli Sprecher ⁎ (pp. 61-67).

GALNT3 encodes UDP-N-acetyl-alpha-d-galactosamine: polypeptide N-acetylgalactosaminyl-transferarase 3 (ppGalNacT3), a glycosyltransferase which has been suggested to prevent proteolysis of FGF23, a potent phosphaturic protein. Accordingly, loss-of-function mutations in GALNT3 cause hyperphosphatemic familial tumoral calcinosis (HFTC), a rare autosomal recessive disorder manifesting with increased kidney reabsorption of phosphate, resulting in severe hyperphosphatemia and widespread ectopic calcifications. Although these findings definitely attribute a role to ppGalNacT3 in the regulation of phosphate homeostasis, little is currently known about the factors regulating GALNT3 expression. In addition, the effect of decreased GALNT3 expression in peripheral tissues has not been explored so far. In the present study, we demonstrate that GALNT3 expression is under the regulation of a number of factors known to be associated with phosphate homeostasis, including inorganic phosphate itself, calcium and 1,25-dihydroxyvitamin D₃. In addition, we show that decreased GALNT3 expression in human skin fibroblasts leads to increased expression of FGF7 and of matrix metalloproteinases, which have been previously implicated in the pathogenesis of ectopic calcification. Thus, the present data suggest that ppGalNacT3 may play a role in peripheral tissues of potential relevance to the pathogenesis of disorders of phosphate metabolism.

Keywords: Calcinosis; Phosphate; Calcification

Relationships among molecular genetic and respiratory properties of Parkinson's disease cybrid cells show similarities to Parkinson's brain tissues by M. Kathleen Borland; K.P. Mohanakumar; Jeremy D. Rubinstein; Paula M. Keeney; Jing Xie; Roderick Capaldi; Lisa D. Dunham; Patricia A. Trimmer; James P. Bennett Jr. ⁎ (pp. 68-74).

We have studied sporadic Parkinson's disease (sPD) from expression of patient mitochondrial DNA (mtDNA) in neural cells devoid of their own mtDNA, the “cybrid” model. In spite of reproducing several properties of sPD brain, it remains unclear whether sPD cybrid cells reflect more complex sPD brain bioenergetic pathophysiology. We characterized and correlated respiration of intact sPD cybrid cells with electron transport chain (ETC) protein assembly, complex I ETC gene expression and ETC protein levels in sPD brain. We also assayed expression for multiple ETC genes coded by mtDNA and nuclear DNA (nDNA) in sPD cybrid cells and brain. sPD cybrid cells have reduced levels of mtDNA genes, variable compensatory normalization of mitochondrial gene expression and show robust correlations with mitochondrial ETC gene expression in sPD brains. Relationships among ETC protein levels predict impaired complex I-mediated respiration in sPD brain. That sPD cybrid cells and sPD brain samples show very correlated regulation of nDNA and mtDNA ETC transcriptomes suggests similar bioenergetic physiologies. We propose that further insights into sPD pathogenesis will follow elucidation of mechanisms leading to reduced mtDNA gene levels in sPD cybrids. This will require characterization of the abnormalities and dynamics of mtDNA changes propagated through sPD cybrids over time.

Keywords: Parkinson's disease; Mitochondria; Cybrid; Respiration; Complex I; Gene expression

Reduced expression of A-type lamins and emerin activates extracellular signal-regulated kinase in cultured cells by Antoine Muchir; Wei Wu; Howard J. Worman ⁎ (pp. 75-81).

Background: Mutations in genes encoding A-type lamins and emerin cause cardiomyopathy and muscular dystrophy. We previously showed activation of the extracellular signal-regulated kinase (ERK) branch of the mitogen-activated protein kinase (MAPK) cascade in hearts of mice with mutations in these genes. Here, we tested the hypothesis that reducing A-type lamins and emerin in cultured cells activate ERK signaling. Methods: We used siRNA to knockdown A-type lamins and emerin in HeLa and C2C12 cells. Activation of ERK was assessed by immunoblotting and immunofluorescence microscopy with antibodies against phosphorylated protein and by using real-time RT-PCR to measure RNAs encoded by genes for transcription factors stimulated by ERK. Results: Knockdown of A-type lamins and emerin in HeLa and C2C12 stimulated phosphorylation and nuclear translocation of ERK as well as activation of genes encoding downstream transcription factors. A MAPK/ERK kinase (MEK) inhibitor reduced ERK phosphorylation in cells with reduced expression of A-type lamins and emerin. Conclusions: These results provide proof for the hypothesis that altered expression of emerin and A-type lamins activates ERK signaling, which in turn can cause cardiomyopathy. General significance: ERK is a potential target for the pharmacological treatment of cardiomyopathy caused by mutations in the genes encoding emerin and A-type lamins.

Keywords: Abbreviations; ERK; extracellular signal-regulated kinase; JNK; c-; Jun; -N-terminal kinase; MAPK; mitogen-activated protein kinase; MEK; MAPK/ERK kinase; OD; optical densityNuclear envelope; Nuclear lamina; Lamin; Emerin; Emery-Dreifuss muscular dystrophy

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BBA - Molecular Basis of Disease (v.1792, #1)