title: Granulin knock out zebrafish lack frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis pathology.
abstract: Loss of function mutations in granulin (GRN) are linked to two distinct neurological disorders, frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL). It is so far unknown how a complete loss of GRN in NCL and partial loss of GRN in FTLD can result in such distinct diseases. In zebrafish, there are two GRN homologues, Granulin A (Grna) and Granulin B (Grnb). We have generated stable Grna and Grnb loss of function zebrafish mutants by zinc finger nuclease mediated genome editing. Surprisingly, the grna and grnb single and double mutants display neither spinal motor neuron axonopathies nor a reduced number of myogenic progenitor cells as previously reported for Grna and Grnb knock down embryos. Additionally, grna-/-;grnb-/- double mutants have no obvious FTLD- and NCL-related biochemical and neuropathological phenotypes. Taken together, the Grna and Grnb single and double knock out zebrafish lack any obvious morphological, pathological and biochemical phenotypes. Loss of zebrafish Grna and Grnb might therefore either be fully compensated or only become symptomatic upon additional challenge.
authors.affiliation: Adolf-Butenandt-Institute-Biochemistry, Ludwig-Maximilians University Munich, Munich, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Solchenberger
authors.affiliation: Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Russell
authors.affiliation: Institute of Molecular Immunology, Helmholtz Center Munich, Munich, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.affiliation: Adolf-Butenandt-Institute-Biochemistry, Ludwig-Maximilians University Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.affiliation: Adolf-Butenandt-Institute-Biochemistry, Ludwig-Maximilians University Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Schmid
mesh_terms: D000818:Animals; D001483:Base Sequence; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics*; D055786:Gene Knockout Techniques; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000166:cytology; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics*; D010641:Phenotype; D000077153:Progranulins; D013116:Spinal Cord / Q000166:cytology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D029961:Zebrafish Proteins