Regulation of neural differentiation by normal and mutant (G654A, amyloidogenic) gelsolin.
Gelsolin belongs to a family of proteins that modulate the structural dynamics of cytoskeletal actin. Gelsolin activity is required for the redistribution of actin occurring during membrane ruffling, cell crawling, and platelet activation. A point mutation (G654A) in the gelsolin gene causes a dominantly inherited systemic amyloidosis called familial amyloidosis of the Finnish type (FAF). This disease is characterized by a cranial neuropathy that cannot be explained solely by amyloid deposits. To address the question of whether gelsolin has a specific role in neural cell development, we transfected cDNA for wild type and G654A point-mutated gelsolin into a neural cell line, Paju, which can be induced to differentiate by treatment with phorbol 12-myristate 13-acetate. Overexpressed wild type gelsolin inhibited neural differentiation whereas mutated gelsolin did not, indicating that appropriate gelsolin activity is essential for neural sprouting. The G654A mutant gelsolin induced stabilization of F-actin and reduced the plasticity of neural development. This provides a novel etiopathogenetic mechanism for the neuronal dysfunction in FAF.
Westberg
J A
JA
Department of Pathology, Helsinki University Hospital and Haartman Institute, University of Helsinki, Finland Karolinska Institute and Hospital, Stockholm, Sweden.
Zhang
K Z
KZ
Andersson
L C
LC
D000293:Adolescent; D017772:Amyloid Neuropathies / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D005260:Female; D018260:Gelsolin / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D017354:Point Mutation; D011994:Recombinant Proteins / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
D018260:Gelsolin; D011994:Recombinant Proteins; D013755:Tetradecanoylphorbol Acetate