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EMBO Molecular Medicine

All articles accepted from 14 August 2012 are published under the terms of the Creative Commons Attribution License.   Articles accepted before this date were published under the agreement as stated in the final article.

Cover image for Vol. 8 Issue 4

Edited By: Stefanie Dimmeler (Chief Editor), Roberto Buccione and Céline Carret (EMBO Editors)

Online ISSN: 1757-4684

Virtual Issue: Neurodegeneration

From molecular details of neurodegenerative diseases to original drug delivery and biomarkers, with insights into Parkinson's and Alzheimer's disease, we have packed this virtual issue with great articles covering primary research but also reviews and highlighted papers. We hope you enjoy delving into this concentration of most exciting insights and future perspectives in Neurodegeneration!

 


Tyrosine kinase inhibition increases functional parkin-Beclin-1 interaction and enhances amyloid clearance and cognitive performance
Irina Lonskaya, Michaeline L. Hebron, Nicole M. Desforges, Alexander Franjie and Charbel E.-H. Moussa
EMBO Mol Med 2013, 5(8), 1247–1262

EMBO Molecular Medicine - Tyrosine kinase inhibition increases functional parkin-Beclin-1 interaction and enhances amyloid clearance and cognitive performance

Two FDA-approved tyrosine kinase inhibitor drugs, Bosutinib and Nilotinib, are shown to ameliorate Alzheimer's disease pathology in mouse models by increasing soluble parkin and leading to amyloid clearance and cognitive improvement.


Caudo-rostral brain spreading of a-synuclein through vagal connections
Ayse Ulusoy, Raffaella Rusconi, Blanca I. Pérez-Revuelta, Ruth E. Musgrove, Michael Helwig, Bettina Winzen-Reichert and Donato A. Di Monte
EMBO Mol Med 2013, 5(7), 1119–1127

EMBO Molecular Medicine - Caudo-rostral brain spreading of a-synuclein through vagal connections

α-synuclein lesions spreading in the brain is characteristic of Parkinson's disease and used to stage the disease severity. Here, a new rat model can explain the caudo-rostral pattern of disease progression providing insights into PD pathogenesis.


A TSPO ligand is protective in a mouse model of multiple sclerosis
Daniel J. Daugherty, Vimal Selvaraj, Olga V. Chechneva, Xiao-Bo Liu, David E. Pleasure and Wenbin Deng
EMBO Mol Med 2013, 5(6), 891–903

EMBO Molecular Medicine - A TSPO ligand is protective in a mouse model of multiple sclerosis

The Authors report on the novel neuroprotective and anti-inflammatory effect of etifoxine, a clinically available drug that is a mitochondrial TSPO ligand, against autoimmune demyelination in an experimental model of multiple sclerosis.


Next generation therapeutics for Alzheimer's disease
Dale E. Bredesen and Varghese John
EMBO Mol Med 2013, 5(6), 795–798

EMBO Molecular Medicine - Next generation therapeutics for Alzheimer's disease

No truly effective therapy has been developed for Alzheimer's disease or mild cognitive impairment. This Perspective discusses how it may be be instructive to consider the successful multi-therapy approaches to other chronic illnesses.


Amyloid precursor protein controls cholesterol turnover needed for neuronal activity
Nathalie Pierrot, Donatienne Tyteca, Ludovic D'auria, Ilse Dewachter, Philippe Gailly, Aurélie Hendrickx, Bernadette Tasiaux, Laetitia El Haylani, Nathalie Muls, Francisca N'Kuli, Annie Laquerrière, Jean-Baptiste Demoulin, Dominique Campion, Jean-Pierre Brion, Pierre J. Courtoy, Pascal Kienlen-Campard and Jean-Noël Octave
EMBO Mol Med 2013, 5(4), 608–625

EMBO Molecular Medicine - Amyloid precursor protein controls cholesterol turnover needed for neuronal activity

GWAS identified components of the cholesterol metabolism machinery as important risk factors for Alzheimer's disease. APP is shown here to control neuronal cholesterol turnover, which highlight therapeutic alternatives for AD treatment.


Lis1 controls dynamics of neuronal filopodia and spines to impact synaptogenesis and social behaviour
Anamaria Sudarov, Frank Gooden, Debbie Tseng, Wen-Biao Gan and Margaret Elizabeth Ross
EMBO Mol Med 2013, 5(4), 591–607

EMBO Molecular Medicine - Lis1 controls dynamics of neuronal filopodia and spines to impact synaptogenesis and social behaviour

Partial loss of Lis1 causes lissencephaly. Here, the authors show that Lis1 is important for the dynamics of neuronal protrusions in synapse formation and maturation and establish a link between Lis1 gene function and autistic-like behaviors in mice.


SIRT1 and SIRT2: emerging targets in neurodegeneration
Gizem Donmez and Tiago F. Outeiro
EMBO Mol Med 2013, 5(3), 344–352

EMBO Molecular Medicine - SIRT1 and SIRT2: emerging targets in neurodegeneration

Sirtuins (SIRTs) are NAD-dependent protein deacetylases, which have been implicated in age-related diseases. This review discusses recent findings on the roles of SIRT1 and SIRT2 in neurodegenerative diseases and in potential therapeutic approaches.


The Huntington disease protein accelerates breast tumour development and metastasis through ErbB2/HER2 signalling
Cristovão Moreira Sousa, John Russel McGuire, Morgane Sonia Thion, David Gentien, Pierre de la Grange, Sophie Tezenas du Montcel, Anne Vincent-Salomon, Alexandra Durr, Sandrine Humbert
EMBO Mol Med 2013, 5(2), 309–325

EMBO Molecular Medicine - The Huntington disease protein accelerates breast tumour development and metastasis through ErbB2/HER2 signalling

Mutant huntingtin accelerates tumorigenesis in mouse breast cancer models, increases epithelial-mesenchymal transition of cancer cells and thus favours lung metastasis in mice.


Spliceosome integrity is defective in the motor neuron diseases ALS and SMA
Hitomi Tsuiji, Yohei Iguchi, Asako Furuya, Ayane Kataoka, Hiroyuki Hatsuta, Naoki Atsuta, Fumiaki Tanaka, Yoshio Hashizume, Hiroyasu Akatsu, Shigeo Murayama, Gen Sobue, Koji Yamanaka
EMBO Mol Med 2013, 5(2), 221–234

EMBO Molecular Medicine - Spliceosome integrity is defective in the motor neuron diseases ALS and SMA

This paper reveals the importance of nuclear Gems and spliceosomal U snRNPs in motor neuron survival common to ALS and SMA.


MicroRNAs in age-related diseases
Stefanie Dimmeler and Pierluigi Nicotera
EMBO Mol Med 2013, 5(2), 180–190

EMBO Molecular Medicine - MicroRNAs in age-related diseases

MicroRNAs have been implicated in the aging process. This review discusses recent findings on the roles of microRNAs in conditions associated with aging, with a focus on cardiovascular and neurodegenerative diseases.


Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease
Nambirajan Govindarajan, Pooja Rao, Susanne Burkhardt, Farahnaz Sananbenesi, Oliver M. Schlüter, Frank Bradke, Jianrong Lu, André Fischer
EMBO Mol Med 2013, 5(1), 52–63

EMBO Molecular Medicine - Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease

The authors identified HDAC6 as a novel therapeutic target in Alzheimer's disease. Reducing HDAC6 protein levels in the brains of an AD mouse model improves memory and protects neurons against amyloid-ß-induced impairment of mitochondrial trafficking.


Thioredoxin-80 is a product of alpha-secretase cleavage that inhibits amyloid-beta aggregation and is decreased in Alzheimer’s disease brain
Francisco Gil-Bea, Susanne Akterin, Torbjörn Persson, Laura Mateos, Anna Sandebring, Javier Avila-Cariño, Angel Gutierrez-Rodriguez, Erik Sundström, Arne Holmgren, Bengt Winblad, Angel Cedazo-Minguez
EMBO Mol Med 2012, 4(10), 1097-1111



The endogenous antioxidant thioredoxin-80 is cleaved from thioredoxin-1 by alpha-secretases and its level is strongly reduced in brain and cerebrospinal fluid from Alzheimer's disease patients suggesting its potential as a valuable biomarker. Since it inhibits amyloidbeta aggregation, it might play a role in AD pathogenesis.


β-Secretase (BACE1) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment
Jun Cai, Xiaoping Qi, Norbert Kociok, Sergej Skosyrski, Alonso Emilio, Qing Ruan, Song Han, Li Liu, Zhijuan Chen, Catherine Bowes Rickman, Todd Golde, Maria B. Grant, Paul Saftig, Lutgarde Serneels, Bart de Strooper, Antonia M. Joussen, Michael E. Boulton
EMBO Mol Med 2012, 4(9), 980-991



BACE1 inhibitors block amyloid precursor protein cleavage and are promising therapeutic agents in Alzheimer's disease. However, lack of BACE1 in the retina has serious detrimental consequences, as shown here, highlighting the need to carefully monitor potential side effects.


Cholinergic-associated loss of hnRNP-A/B in Alzheimer’s disease impairs cortical splicing and cognitive function in mice
Amit Berson, Shahar Barbash, Galit Shaltiel, Yael Goll, Geula Hanin, David S. Greenberg, Maya Ketzef, Albert J. Becker, Alon Friedman, Hermona Soreq
EMBO Mol Med 2012, 4(8), 730-742



Increasing evidence link RNA metabolism to neurodegenerative disease. In this paper, the authors report that sporadic Alzheimer's disease involves selective loss of hnRNP A/B splicing factors resulting in dendrite loss and impaired neuronal functioning.


Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic alzheimer’s disease
Francesc X. Guix, Tina Wahle, Kristel Vennekens, An Snellinx, Lucia Chavez-Gutierrez, Gerard Ill-Raga, Eva Ramos, Cristina Guardia-Laguarta, Alberto Lleó, Muriel Arimon, Oksana Berezovska, Francisco J. Muñoz, Carlos G. Dotti, Bart De Strooper
EMBO Mol Med 2012, 4(7), 660-673



Despite the fact that Alzheimer's disease (AD) is strongly associated with increased age, we still lack a molecular explanation to link aging with any of the known pathways causing AD. Here, the authors show that nitrosative stress is a major effector of the increased Aβ42/Aβ40 ratio in old neurons through modification of γ-secretase, providing a putative therapeutic target for both inherited and late-onset AD.


Novel APP/Aβ mutation K16N produces highly toxic heteromeric Aβ oligomers
Daniela Kaden, Anja Harmeier, Christoph Weise, Lisa M. Munter, Veit Althoff, Benjamin R. Rost, Peter W. Hildebrand, Dietmar Schmitz, Michael Schaefer, Rudi Lurz, Sabine Skodda, Raina Yamamoto, Sönke Arlt, Ulrich Finckh, Gerd Multhaup
EMBO Mol Med 2012, 4(7), 647-659



Direct genomic sequencing of APP exons 16 and 17 in a 53-year old patient with early-onset dementia identified a novel mutation in the penultimate codon of exon 16. Repeated cerebrospinal fluid analysis suggested Alzheimer-type Neurodegeneration. Through functional assays, the novel K16N mutation (located at the α- secretase cleavage site) reduces α-secretase processing and affects both APP processing and Aβ peptide properties.


β- but not α-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia
Robert Tamayev, Shuji Matsuda, Ottavio Arancio, Luciano D’Adamio
EMBO Mol Med 2012, 4(3), 171-179



Direct genomic sequencing of APP exons 16 and 17 in a 53-year old patient with early-onset dementia identified a novel mutation in the penultimate codon of exon 16. Repeated cerebrospinal fluid analysis suggested Alzheimer-type Neurodegeneration. Through functional assays, the novel K16N mutation (located at the α- secretase cleavage site) reduces α-secretase processing and affects both APP processing and Aβ peptide properties.


Impaired Coenzyme A metabolism affects histone and tubulin acetylation in Drosophila and human cell models of pantothenate kinase associated neurodegeneration
Katarzyna Siudeja, Balaji Srinivasan, Lanjun Xu, Anil Rana, Jannie de Jong, Ellen A. A. Nollen, Suzanne Jackowski, Lynn Sanford, Susan Hayflick, Ody C. M. Sibon
EMBO Mol Med 2011, 3(12), 755-766



Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a severe genetic and mostly early childhood onset disease, for which no treatment is currently available. Reduced CoA levels found in fly and human cell models result in reduced histone and tubulin acetylation. Restoration of acetylation levels partially rescues the PKAN associated phenotypes, suggesting possible treatment strategies.


Amyloid precursor protein mutation E682K at the alternative β-secretase cleavage β'-site increases Aβ generation
Lujia Zhou, Nathalie Brouwers, Iryna Benilova, Annelies Vandersteen, Marc Mercken, Koen Van Laere, Philip Van Damme, David Demedts, Fred Van Leuven, Kristel Sleegers, Kerensa Broersen, Christine Van Broeckhoven, Rik Vandenberghe, Bart De Strooper
EMBO Mol Med 2011, 3(5), 291-302



This work first demonstrates that β'-site cleavage of human APP is a major event in neurons and plays a 'protective' role in APP metabolism, while disruption of this cleavage by mutation or other effects will enhance the amyloidogenic processing of APP and may consequentially lead to Alzheimer's disease. Our work shows how a combination of clinical and cell biological methods works to determine the possible pathogenicity of novel mutations identified in single families when segregation-based evidence is not available.

Accompanying Closeup
A new way APP mismetabolism can lead to Alzheimer's disease
John Hardy, Rita Guerreiro
EMBO Mol Med 2011, 3(5), 247-248


Systemic low-molecular weight drug delivery to pre-selected neuronal regions
Matthew Campbell, Marian M. Humphries, Anna-Sophia Kiang, Anh T. H. Nguyen, Oliviero L. Gobbo, Lawrence C. S. Tam, Mayu Suzuki, Finnian Hanrahan, Ema Ozaki, G.-Jane Farrar, Paul F. Kenna, Peter Humphries
EMBO Mol Med 2011, 3(4), 235-245



Up to 98% of systemically deliverable low-molecular weight drugs, many of which could be used in treatment and prevention of the world's most common neurodegenerative and vision-threatening disorders, are not in current clinical use because they cannot cross the so-called Blood Brain Barrier (BBB) and inner Blood Retina Barrier (iBRB). In this article, the authors have developed an AAV-2/9 vector, expressing an inducible shRNA designed to downregulate transcripts encoding a tight junction protein expressed in the brain and retinal microvasculatures, modulating the iBRB and the BBB to allow passive diffusion of small molecules from the blood into the neural retina or brain.


To live or to die: a matter of processing damaged DNA termini in neurons
Sherif F. El-Khamisy
EMBO Mol Med 2011, 3(2), 78-88



Defects in the repair of deoxyribonucleic acid (DNA) damage underpin several hereditary neurological diseases in humans. Of the different activities that repair chromosomal DNA breaks, defects in resolving damaged DNA termini are among the most common causes of neuronal cell death. Here, the molecular mechanisms of some of the DNA end processing activities are reviewed and the association with human neurodegenerative disease is discussed.


Mitochondrial fission and cristae disruption increase the response of cell models of Huntington's disease to apoptotic stimuli
Veronica Costa, Marta Giacomello, Roman Hudec, Raffaele Lopreiato, Gennady Ermak, Dmitri Lim, Walter Malorni, Kelvin J. A. Davies, Ernesto Carafoli, Luca Scorrano
EMBO Mol Med 2010, 2(12), 490-503



Huntington's disease (HD) is a genetic, progressive, neurodegenerative disease caused by the expansion of a polyglutamine trait in the Huntingtin protein. The main neurological signs and symptoms are caused by the loss of the medium spiny neurons of the striatum. The exact pathogenesis of the disease is unknown but mitochondria, which are positioned at the crossroad of energy production and control of cell death, have been heavily implicated. Here, the authors demonstrate that a feed-forward loop of mitochondrial fragmentation and alterations of their ultrastructure play an important role in determining the susceptibility of HD cellular models to apoptosis.

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Could successful (mitochondrial) networking help prevent Huntington's disease?
Jorge M. A. Oliveira, Robert N. Lightowlers
EMBO Mol Med 2010, 2(12), 487-489


Prion protein and Aβ-related synaptic toxicity impairment
Anna Maria Calella, Mélissa Farinelli, Mario Nuvolone, Osvaldo Mirante, Rita Moos, Jeppe Falsig, Isabelle M. Mansuy, Adriano Aguzzi
EMBO Mol Med 2010, 2(8), 306-314



Alzheimer's disease (AD), the most common neurodegenerative disorder, culminates in cognitive decline with limited treatment options. Aggregated Aβ, possibly in the form of oligomers, accumulates in the brain of affected individuals and may drive AD pathogenesis by activating ill-defined signaling pathways. The results reported here suggest that PrPC may not be a universal mediator of Aβ synaptotoxicity.

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Prion protein in Alzheimer's pathogenesis: a hot and controversial issue
Iryna Benilova, Bart De Strooper
EMBO Mol Med 2010, 2(8), 289-290


Cerebrospinal fluid tau and ptau181 increase with cortical amyloid deposition in cognitively normal individuals: Implications for future clinical trials of Alzheimer's disease
Anne M. Fagan, Mark A. Mintun, Aarti R. Shah, Patricia Aldea, Catherine M. Roe, Robert H. Mach, Daniel Marcus, John C. Morris, David M. Holtzman
EMBO Mol Med 2009, 1(8-9), 371-380



Alzheimer's disease (AD) pathology is estimated to develop many years before detectable cognitive decline. Fluid and imaging biomarkers may identify people in early symptomatic and even preclinical stages, possibly when potential treatments can best preserve cognitive function. In this article, the authors suggest that changes in brain Aβ42 metabolism and amyloid formation are early pathogenic events in AD, and that significant disruptions in CSF tau metabolism likely occur after Aβ42 initially aggregates and increases as amyloid accumulates. These findings have important implications for preclinical AD diagnosis and treatment.


PINK1 function in health and disease
Emma Deas, Helene Plun-Favreau, Nicholas W. Wood
EMBO Mol Med 2009, 1(3), 152-165



The role of mitochondria in sporadic Parkinson's disease (PD) has been debated for a little over 20 years since the description of complex I deficiency in the substantia nigra pars compacta of PD patients. However, the identification of recessive pathogenic mutations in the pink1 gene in familial PD cases firmly re-ignited interest in the pathophysiology of mitochondria in PD. PINK1 protects cells against oxidative stress induced apoptosis. In this review, the authors summarize the physiological roles that have been assigned to PINK1 and the potential mechanisms behind pathogenesis.


Parkinson's disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function
Vanessa A. Morais, Patrik Verstreken, Anne Roethig, Joél Smet, An Snellinx, Mieke Vanbrabant, Dominik Haddad, Christian Frezza, Wim Mandemakers, Daniela Vogt-Weisenhorn, Rudy Van Coster, Wolfgang Wurst, Luca Scorrano, Bart De Strooper
EMBO Mol Med 2009, 1(2), 99-111



Parkinson's disease (PD) is a common progressive neurodegenerative disorder which etiology remains unknown despite evidence pointing to the involvement of abnormal protein aggregation, oxidative stress and mitochondrial dysfunction. The recessive PD gene PINK1, a mitochondrial serine/threonine kinase, appears to affect the mitochondrial dynamics. Using Drosophila and mouse models, the authors show here that an early effect of PINK1 deficiency is the disruption of Complex I function, which results in mitochondrial membrane depolarization, increased sensitivity to apoptotic stress and synaptic transmission deficits in Drosophila neurons.

Accompanying Closeup
In a flurry of PINK, mitochondrial bioenergetics takes a leading role in Parkinson's disease
Anne N. Murphy
EMBO Mol Med 2009, 1(2), 81-84

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