Abstract:
:Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are relentlessly progressive neurodegenerative disorders with overlapping clinical, genetic and pathological features. Cytoplasmic inclusions of fused in sarcoma (FUS) are the hallmark of several forms of FTLD and ALS patients with mutations in the FUS gene. FUS is a multifunctional, predominantly nuclear, DNA and RNA binding protein. Here, we report that transgenic mice overexpressing wild-type human FUS develop an aggressive phenotype with an early onset tremor followed by progressive hind limb paralysis and death by 12 weeks in homozygous animals. Large motor neurons were lost from the spinal cord accompanied by neurophysiological evidence of denervation and focal muscle atrophy. Surviving motor neurons in the spinal cord had greatly increased cytoplasmic expression of FUS, with globular and skein-like FUS-positive and ubiquitin-negative inclusions associated with astroglial and microglial reactivity. Cytoplasmic FUS inclusions were also detected in the brain of transgenic mice without apparent neuronal loss and little astroglial or microglial activation. Hemizygous FUS overexpressing mice showed no evidence of a motor phenotype or pathology. These findings recapitulate several pathological features seen in human ALS and FTLD patients, and suggest that overexpression of wild-type FUS in vulnerable neurons may be one of the root causes of disease. Furthermore, these mice will provide a new model to study disease mechanism, and test therapies.
journal_name
Acta Neuropatholjournal_title
Acta neuropathologicaauthors
Mitchell JC,McGoldrick P,Vance C,Hortobagyi T,Sreedharan J,Rogelj B,Tudor EL,Smith BN,Klasen C,Miller CC,Cooper JD,Greensmith L,Shaw CEdoi
10.1007/s00401-012-1043-zsubject
Has Abstractpub_date
2013-02-01 00:00:00pages
273-88issue
2eissn
0001-6322issn
1432-0533journal_volume
125pub_type
杂志文章abstract::The gastrocnemius muscles of 3 groups of 10 rats, sacrified 5, 7, and 12 days respectively, following tenotomy, were submitted to different types of fixation, fixative and embedding. The occurrence of target fibres is shown not to be an artefact due to the histological procedures. Further examination demonstrates that...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00690981
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journal_title:Acta neuropathologica
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doi:10.1007/BF00308960
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journal_title:Acta neuropathologica
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journal_title:Acta neuropathologica
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pub_type: 杂志文章,评审
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journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s004010051075
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journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00690990
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journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s004010051022
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journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00690850
更新日期:1979-05-15 00:00:00
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journal_title:Acta neuropathologica
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更新日期:2010-12-01 00:00:00
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journal_title:Acta neuropathologica
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journal_title:Acta neuropathologica
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journal_title:Acta neuropathologica
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journal_title:Acta neuropathologica
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journal_title:Acta neuropathologica
pub_type: 杂志文章
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journal_title:Acta neuropathologica
pub_type: 杂志文章
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