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Neuropathological Abnormalities in Transgenic Mice Harbouring a Phosphorylation Mutant Neurofilament Transgene
Author(s) -
Gibb Barry J. M.,
Brion JeanPierre,
Brownlees Janet,
Anderton Brian H.,
Miller Christopher C. J.
Publication year - 1998
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1998.70020492.x
Subject(s) - transgene , neurofilament , mutant , genetically modified mouse , phosphorylation , biology , microbiology and biotechnology , neuroscience , genetics , gene , immunohistochemistry , immunology
Ser 55 within the head domain of neurofilament light chain (NF‐L) is a target for phosphorylation by protein kinase A. To understand further the physiological role(s) of NF‐L Ser 55 phosphorylation, we generated transgenic mice with a mutant NF‐L transgene in which Ser 55 was mutated to Asp so as to mimic permanent phosphorylation. Two lines of NF‐L(Asp) mice were created and these animals express the transgene in many neurones of the central and peripheral nervous systems. Both transgenic lines display identical, early onset, and robust pathological changes in the brain. These involve the formation of NF‐L(Asp)‐containing perikaryal neurofilament inclusion bodies and the development of swollen Purkinje cell axons. Development of these pathologies was rapid and fully established in mice as young as 4 weeks of age. The two transgenic lines show no elevation of NF‐L, neurofilament middle chain (NF‐M), or neurofilament heavy chain (NF‐H), and transgenic NF‐L(Asp) represents only a minor proportion of total NF‐L protein. Because other published transgenic lines expressing higher levels of wild‐type NF‐L do not exhibit phenotypic changes that in any way resemble those in the NF‐L(Asp) mice and because the two different NF‐L(Asp) transgenic lines display identical neuropathological changes, it is likely that the pathological alterations observed in the NF‐L(Asp) mice are the result of properties of the mutant NF‐L. These results support the notion that phosphorylation of Ser 55 is a mechanism for regulating neurofilament organisation in vivo.