Granulin knock out zebrafish lack frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis pathology

Barbara Solchenberger; Claire Russell; Elisabeth Kremmer; Christian Haass; Bettina Schmid

doi:10.1371/journal.pone.0118956

Granulin knock out zebrafish lack frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis pathology

PLoS One. 2015 Mar 18;10(3):e0118956. doi: 10.1371/journal.pone.0118956. eCollection 2015.

Authors

Barbara Solchenberger¹, Claire Russell², Elisabeth Kremmer³, Christian Haass⁴, Bettina Schmid⁴

Affiliations

¹ Adolf-Butenandt-Institute-Biochemistry, Ludwig-Maximilians University Munich, Munich, Germany.
² Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom.
³ Institute of Molecular Immunology, Helmholtz Center Munich, Munich, Germany.
⁴ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
Female
Frontotemporal Lobar Degeneration / genetics*
Gene Knockout Techniques*
Humans
Intercellular Signaling Peptides and Proteins / deficiency*
Intercellular Signaling Peptides and Proteins / genetics*
Male
Molecular Sequence Data
Motor Neurons / cytology
Mutation
Neuronal Ceroid-Lipofuscinoses / genetics*
Phenotype
Progranulins
Spinal Cord / cytology
Zebrafish Proteins / deficiency
Zebrafish Proteins / genetics
Zebrafish*

Substances

Intercellular Signaling Peptides and Proteins
Progranulins
Zebrafish Proteins

Grants and funding

This work was supported by the Sonderforschungsbereich 596, International Max Planck Research School for Molecular and Cellular Life Sciences (B. So.), the Elite Network of Bavaria (B. So.), a Short Term Scientific Mission COST Action BM0804 (B.So.), the Batten Disease Family Association (C.R.), the European Research Council under the European Union’s Seventh Framework Program FP7/2007–2013)/ ERC Grant Agreement No. 321366-Amyloid (advanced grant to C.H.), the general legacy of Mrs. Ammer (to the Ludwig-Maximilians University/ C.H.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.