Publication Date:
2015-05-16
Description:
The major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis is a G4C2 repeat expansion in C9ORF72. Efforts to combat neurodegeneration associated with "c9FTD/ALS" are hindered by a lack of animal models recapitulating disease features. We developed a mouse model to mimic both neuropathological and clinical c9FTD/ALS phenotypes. We expressed (G4C2)66 throughout the murine central nervous system by means of somatic brain transgenesis mediated by adeno-associated virus. Brains of 6-month-old mice contained nuclear RNA foci, inclusions of poly(Gly-Pro), poly(Gly-Ala), and poly(Gly-Arg) dipeptide repeat proteins, as well as TDP-43 pathology. These mouse brains also exhibited cortical neuron and cerebellar Purkinje cell loss, astrogliosis, and decreased weight. (G4C2)66 mice also developed behavioral abnormalities similar to clinical symptoms of c9FTD/ALS patients, including hyperactivity, anxiety, antisocial behavior, and motor deficits.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692360/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692360/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chew, Jeannie -- Gendron, Tania F -- Prudencio, Mercedes -- Sasaguri, Hiroki -- Zhang, Yong-Jie -- Castanedes-Casey, Monica -- Lee, Chris W -- Jansen-West, Karen -- Kurti, Aishe -- Murray, Melissa E -- Bieniek, Kevin F -- Bauer, Peter O -- Whitelaw, Ena C -- Rousseau, Linda -- Stankowski, Jeannette N -- Stetler, Caroline -- Daughrity, Lillian M -- Perkerson, Emilie A -- Desaro, Pamela -- Johnston, Amelia -- Overstreet, Karen -- Edbauer, Dieter -- Rademakers, Rosa -- Boylan, Kevin B -- Dickson, Dennis W -- Fryer, John D -- Petrucelli, Leonard -- P01 NS084974/NS/NINDS NIH HHS/ -- P01NS084974/NS/NINDS NIH HHS/ -- P50 AG016574/AG/NIA NIH HHS/ -- P50AG016574/AG/NIA NIH HHS/ -- R01 NS077402/NS/NINDS NIH HHS/ -- R01ES20395/ES/NIEHS NIH HHS/ -- R01NS063964/NS/NINDS NIH HHS/ -- R01NS077402/NS/NINDS NIH HHS/ -- R01NS088689/NS/NINDS NIH HHS/ -- R21 NS084528/NS/NINDS NIH HHS/ -- R21NS079807/NS/NINDS NIH HHS/ -- R21NS084528/NS/NINDS NIH HHS/ -- R21NS089979/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jun 5;348(6239):1151-4. doi: 10.1126/science.aaa9344. Epub 2015 May 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. ; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. ; Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. ; German Center for Neurodegenerative Diseases (DZNE) Munich, Feodor-Lynen-Strasse 17, 81337 Munich, Germany. Institute for Metabolic Biochemistry, Ludwig-Maximilians University Munich, Feodor-Lynen-Strasse 17, 81337 Munich, Germany. Munich Cluster of Systems Neurology (SyNergy), Munich, Germany. ; Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. petrucelli.leonard@mayo.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25977373" target="_blank"〉PubMed〈/a〉
Keywords:
Amyotrophic Lateral Sclerosis/*genetics/pathology
;
Animals
;
Antisocial Personality Disorder/genetics/pathology
;
Cerebral Cortex/metabolism/pathology
;
DNA-Binding Proteins/*genetics
;
Dependovirus
;
Dipeptides/metabolism
;
*Disease Models, Animal
;
Frontotemporal Dementia/*genetics/pathology
;
Gene Transfer Techniques
;
HEK293 Cells
;
Humans
;
*Mice
;
Proteins/*genetics
;
Purkinje Cells/metabolism/pathology
;
RNA, Nuclear/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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