Anp32e/Cpd1 regulates protein phosphatase 2A activity at synapses during synaptogenesis.
Anp32e/Cpd1, a member of the acidic nuclear phosphoprotein (Anp)32 family, is characterized by the presence of an amino terminal domain containing four leucine-rich repeats and a carboxyl-terminal low-compositional complexity acidic region. In previous studies performed to understand the biological role of Anp32e/Cpd1, we showed a predominant presence of Anp32e/Cpd1 in the nucleus. However, when Anp32e/Cpd1 is in the cytoplasm, it co-localizes spatially with protein phosphatase 2A (PP2A) near cell membranes, far from the synapses. In the present work, we show that Anp32e/Cpd1 is also present as a membrane-bound 74/76-kDa protein with a widespread distribution in the brain. We reveal that the expression, synthesis and half-life of this high-molecular-weight form of Anp32e/Cpd1 are spatially and temporally correlated with the cerebellar synaptogenesis period. We demonstrate that synaptic Anp32e/Cpd1 co-localizes, interacts and inhibits PP2A activity, and that phosphorylation of Anp32/Cpd1 is required for the Anp32e-PP2A interaction. Also, subcellular localization was shown with electronic microscopy. Finally, we examine Anp32e/Cpd1 and PP2A distribution in two ataxic mutant models, weaver and staggerer, and show that their co-localization in Purkinje cell dendrites depends on parallel fibre/Purkinje cell contacts. Based on these observations, we propose that Anp32e/Cpd1 mediates synaptogenesis process by modulating PP2A activity.
Costanzo
Roxana V
RV
Centro Nacional de Genética Médica, A.N.L.I.S, Programa Nacional de Genética Médica, Avenue, Las Heras 2670 (1425), Buenos Aires, Argentina.
Vilá-Ortíz
Guillermo J
GJ
Perandones
Claudia
C
Carminatti
Héctor
H
Matilla
Antoni
A
Radrizzani
Martín
M
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D016253:Microscopy, Immunoelectron / Q000379:methods; D018832:Molecular Chaperones; D008970:Molecular Weight; D009419:Nerve Tissue Proteins / Q000502:physiology*; D038081:Organogenesis; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D054648:Protein Phosphatase 2; D013347:Subcellular Fractions / Q000378:metabolism / Q000648:ultrastructure; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure
C435730:Anp32e protein, mouse; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2