title: Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion.
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.
authors.affiliation: Department of Clinical Neuroscience, Kings College London, King's Centre for Neurodegeneration Research, London SE5 8AF, UK.
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Mitchell
authors.forename: Philip
authors.initials: P
authors.lastname: McGoldrick
authors.forename: Caroline
authors.initials: C
authors.lastname: Vance
authors.forename: Tibor
authors.initials: T
authors.lastname: Hortobagyi
authors.forename: Jemeen
authors.initials: J
authors.lastname: Sreedharan
authors.forename: Boris
authors.initials: B
authors.lastname: Rogelj
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Tudor
authors.forename: Bradley N
authors.initials: BN
authors.lastname: Smith
authors.forename: Christian
authors.initials: C
authors.lastname: Klasen
authors.forename: Christopher C J
authors.initials: CC
authors.lastname: Miller
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cooper
authors.forename: Linda
authors.initials: L
authors.lastname: Greensmith
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D018628:Gene Dosage; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000473:pathology; D007537:Isometric Contraction / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016472:Motor Neuron Disease / Q000235:genetics* / Q000473:pathology*; D009046:Motor Neurons / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D010243:Paralysis / Q000235:genetics / Q000473:pathology; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000473:pathology
chemical_list: D034702:RNA-Binding Protein FUS