| Records |
| Author |
Lacovich, V.; Espindola, S.L.; Alloatti, M.; Pozo Devoto, V.; Cromberg, L.E.; Carna, M.E.; Forte, G.; Gallo, J.-M.; Bruno, L.; Stokin, G.B.; Avale, M.E.; Falzone, T.L. |
| Title |
Tau Isoforms Imbalance Impairs the Axonal Transport of the Amyloid Precursor Protein in Human Neurons |
Type |
Journal Article |
| Year |
2017 |
Publication |
The Journal of Neuroscience : the Official Journal of the Society for Neuroscience |
Abbreviated Journal |
J Neurosci |
| Volume |
37 |
Issue |
1 |
Pages |
58-69 |
| Keywords |
App; Alzheimer's; axonal transport; splicing; tau; tauopathies |
| Abstract |
Tau, as a microtubule (MT)-associated protein, participates in key neuronal functions such as the regulation of MT dynamics, axonal transport, and neurite outgrowth. Alternative splicing of exon 10 in the tau primary transcript gives rise to protein isoforms with three (3R) or four (4R) MT binding repeats. Although tau isoforms are balanced in the normal adult human brain, imbalances in 3R:4R ratio have been tightly associated with the pathogenesis of several neurodegenerative disorders, yet the underlying molecular mechanisms remain elusive. Several studies exploiting tau overexpression and/or mutations suggested that perturbations in tau metabolism impair axonal transport. Nevertheless, no physiological model has yet demonstrated the consequences of altering the endogenous relative content of tau isoforms over axonal transport regulation. Here, we addressed this issue using a trans-splicing strategy that allows modulating tau exon 10 inclusion/exclusion in differentiated human-derived neurons. Upon changes in 3R:4R tau relative content, neurons showed no morphological changes, but live imaging studies revealed that the dynamics of the amyloid precursor protein (APP) were significantly impaired. Single trajectory analyses of the moving vesicles showed that predominance of 3R tau favored the anterograde movement of APP vesicles, increasing anterograde run lengths and reducing retrograde runs and segmental velocities. Conversely, the imbalance toward the 4R isoform promoted a retrograde bias by a significant reduction of anterograde velocities. These findings suggest that changes in 3R:4R tau ratio has an impact on the regulation of axonal transport and specifically in APP dynamics, which might link tau isoform imbalances with APP abnormal metabolism in neurodegenerative processes. SIGNIFICANCE STATEMENT: The tau protein has a relevant role in the transport of cargos throughout neurons. Dysfunction in tau metabolism underlies several neurological disorders leading to dementia. In the adult human brain, two tau isoforms are found in equal amounts, whereas changes in such equilibrium have been associated with neurodegenerative diseases. We investigated the role of tau in human neurons in culture and found that perturbations in the endogenous balance of tau isoforms were sufficient to impair the transport of the Alzheimer's disease-related amyloid precursor protein (APP), although neuronal morphology was normal. Our results provide evidence of a direct relationship between tau isoform imbalance and defects in axonal transport, which induce an abnormal APP metabolism with important implications in neurodegeneration. |
| Address |
Instituto de Biologia y Medicina Experimental (IBYME-CONICET), Buenos Aires C1428ADN, Argentina |
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English |
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| ISSN |
0270-6474 |
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| Notes |
PMID:28053030 |
Approved |
no |
| Call Number |
ref @ user @ |
Serial |
95902 |
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| Author |
Polex-Wolf, J.; Yeo, G.S.H.; O'Rahilly, S. |
| Title |
Impaired prohormone processing: a grand unified theory for features of Prader-Willi syndrome? |
Type |
Journal Article |
| Year |
2017 |
Publication |
The Journal of Clinical Investigation |
Abbreviated Journal |
J Clin Invest |
| Volume |
127 |
Issue |
1 |
Pages |
98-99 |
| Keywords |
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| Abstract |
Prader-Willi syndrome (PWS) is a complex disorder that manifests with an array of phenotypes, such as hypotonia and difficulties in feeding during infancy and reduced energy expenditure, hyperphagia, and developmental delays later in life. While the genetic cause has long been known, it is still not clear how mutations at this locus produce this array of phenotypes. In this issue of the JCI, Burnett and colleagues used a comprehensive approach to gain insight into how PWS-associated mutations drive disease. Using neurons derived from PWS patient induced pluripotent stem cells (iPSCs) and mouse models, the authors provide evidence that neuroendocrine PWS-associated phenotypes may be linked to reduced expression of prohormone convertase 1 (PC1). While these compelling results support a critical role for PC1 deficiency in PWS, more work needs to be done to fully understand how and to what extent loss of this prohormone processing enzyme underlies disease manifestations in PWS patients. |
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English |
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| ISSN |
0021-9738 |
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| Notes |
PMID:27941250 |
Approved |
no |
| Call Number |
ref @ user @ |
Serial |
95907 |
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| Author |
Vershkov, D.; Benvenisty, N. |
| Title |
Human pluripotent stem cells in modeling human disorders: the case of fragile X syndrome |
Type |
Journal Article |
| Year |
2017 |
Publication |
Regenerative Medicine |
Abbreviated Journal |
Regen Med |
| Volume |
12 |
Issue |
1 |
Pages |
53-68 |
| Keywords |
disease modeling; drug discovery; embryonic stem cells; fragile X syndrome; human pluripotent stem cells; neural differentiation |
| Abstract |
Human pluripotent stem cells (PSCs) generated from affected blastocysts or from patient-derived somatic cells are an emerging platform for disease modeling and drug discovery. Fragile X syndrome (FXS), the leading cause of inherited intellectual disability, was one of the first disorders modeled in both embryonic stem cells and induced PCSs and can serve as an exemplary case for the utilization of human PSCs in the study of human diseases. Over the past decade, FXS-PSCs have been used to address the fundamental questions regarding the pathophysiology of FXS. In this review we summarize the methodologies for generation of FXS-PSCs, discuss their advantages and disadvantages compared with existing modeling systems and describe their utilization in the study of FXS pathogenesis and in the development of targeted treatment. |
| Address |
The Azrieli Center for Stem Cells & Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel |
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English |
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Edition |
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| ISSN |
1746-0751 |
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| Notes |
PMID:27900874 |
Approved |
no |
| Call Number |
ref @ user @ |
Serial |
95909 |
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| Author |
Li, M.; Zhao, H.; Ananiev, G.E.; Musser, M.T.; Ness, K.H.; Maglaque, D.L.; Saha, K.; Bhattacharyya, A.; Zhao, X. |
| Title |
Establishment of Reporter Lines for Detecting Fragile X Mental Retardation (FMR1) Gene Reactivation in Human Neural Cells |
Type |
Journal Article |
| Year |
2017 |
Publication |
Stem Cells (Dayton, Ohio) |
Abbreviated Journal |
Stem Cells |
| Volume |
35 |
Issue |
1 |
Pages |
158-169 |
| Keywords |
Drug discovery; Fmr1; Fmrp; Fragile X syndrome; High throughput; Induced pluripotent stem cells; Luciferase |
| Abstract |
Human patient-derived induced pluripotent stem cells (hiPSCs) provide unique opportunities for disease modeling and drug development. However, adapting hiPSCs or their differentiated progenies to high throughput assays for phenotyping or drug screening has been challenging. Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and a major genetic cause of autism. FXS is caused by mutational trinucleotide expansion in the FMR1 gene leading to hypermethylation and gene silencing. One potential therapeutic strategy is to reactivate the silenced FMR1 gene, which has been attempted using both candidate chemicals and cell-based screening. However, molecules that effectively reactivate the silenced FMR1 gene are yet to be identified; therefore, a high throughput unbiased screen is needed. Here we demonstrate the creation of a robust FMR1-Nluc reporter hiPSC line by knocking in a Nano luciferase (Nluc) gene into the endogenous human FMR1 gene using the CRISPR/Cas9 genome editing method. We confirmed that luciferase activities faithfully report FMR1 gene expression levels and showed that neural progenitor cells derived from this line could be optimized for high throughput screening. The FMR1-Nluc reporter line is a good resource for drug screening as well as for testing potential genetic reactivation strategies. In addition, our data provide valuable information for the generation of knockin human iPSC reporter lines for disease modeling, drug screening, and mechanistic studies. Stem Cells 2017;35:158-169. |
| Address |
Department of Neuroscience, University of Wisconsin-Madison, Madison, Wisconsin, USA |
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English |
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Edition |
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| ISSN |
1066-5099 |
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Conference |
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| Notes |
PMID:27422057 |
Approved |
no |
| Call Number |
ref @ user @ |
Serial |
95937 |
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| Author |
Fogel, O.; Richard-Miceli, C.; Tost, J. |
| Title |
Epigenetic Changes in Chronic Inflammatory Diseases |
Type |
Journal Article |
| Year |
2017 |
Publication |
Advances in Protein Chemistry and Structural Biology |
Abbreviated Journal |
Adv Protein Chem Struct Biol |
| Volume |
106 |
Issue |
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Pages |
139-189 |
| Keywords |
Behcet's disease; Crohn's disease; DNA methylation; Ewas; Epigenetics; Histone modifications; Inflammatory bowel disease; Psoriasis; Spondyloarthritis; Ulcerative colitis |
| Abstract |
The number of people diagnosed with chronic inflammatory diseases has increased noteworthy in the last 40 years. Spondyloarthritis (SpA), inflammatory bowel diseases (IBD), and psoriasis are the most frequent chronic inflammatory diseases, resulting from a combination of genetic predisposition and environmental factors. Epigenetic modifications include DNA methylation, histone modifications, and small and long noncoding RNAs. They are influenced by environmental exposure, life-style, and aging and have recently been shown to be altered in many complex diseases including inflammatory diseases. While epigenetic modifications have been well characterized in other diseases such as cancer and autoimmune diseases, knowledge on changes in inflammatory diseases is lagging behind with some disease-specific differences. While the DNA methylation profile of different cell types in patients with IBD has been relatively well described, less is known on changes implicated in psoriasis, and no systematic genome-wide studies have so far been performed in SpA. In this chapter, we review in detail the reported changes in patterns of DNA methylation and posttranslational histone modifications in chronic inflammatory diseases highlighting potential connections between disease-associated pathophysiological changes such as the dysbiosis of the microbiome or genetic variations associated with disease susceptibility and the epigenome. We also discuss important parameters of meaningful epigenetic studies such as the use of well defined, disease-relevant cell populations, and elude on the potential future of engineering of the epigenome in inflammatory diseases. |
| Address |
Laboratory for Epigenetics and Environment, Centre National de Genotypage, CEA-Institut de Genomique, Evry, France. Electronic address: tost@cng.fr |
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English |
Summary Language |
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Original Title |
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Abbreviated Series Title |
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Edition |
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| ISSN |
1876-1623 |
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| Notes |
PMID:28057210 |
Approved |
no |
| Call Number |
ref @ user @ |
Serial |
96374 |
| Permanent link to this record |
