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Homocysteinylation of neuronal proteins contributes to folate deficiency‐associated alterations of differentiation, vesicular transport, and plasticity in hippocampal neuronal cells
Author(s) -
Akchiche Nassila,
BossenmeyerPourié Carine,
Kerek Racha,
Martin Nicolas,
Pourié Grégory,
Koziel Violette,
Helle Déborah,
Alberto JeanMarc,
Ortiou Sandrine,
Camadro JeanMichel,
Léger Thibaut,
Guéant JeanLouis,
Daval JeanLuc
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.12-205757
Subject(s) - transmethylation , microbiology and biotechnology , biology , vesicular transport protein , neurite , hippocampal formation , cell polarity , chemistry , biochemistry , neuroscience , cell , methylation , vesicle , membrane , gene , in vitro
Despite the key role in neuronal development of a deficit in the methyl donor folate, little is known on the underlying mechanisms. We therefore studied the consequences of folate deficiency on proliferation, differentiation, and plasticity of the rat H19‐7 hippocampal cell line. Folate deficit reduced proliferation (17%) and sensitized cells to differentiation‐associated apoptosis (+16%). Decreased production (–58%) of S ‐adenosylmethionine (the universal substrate for transmethylation reactions) and increased expression of histone deacetylases (HDAC4,6,7) would lead to epigenomic changes that may impair the differentiation process. Cell polarity, vesicular transport, and synaptic plasticity were dramatically affected, with poor neurite outgrowth (–57%). Cell treatment by an HDAC inhibitor (SAHA) led to a noticeable improvement of cell polarity and morphology, with longer processes. Increased homocysteine levels (+55%) consecutive to folate shortage produced homocysteinylation, evidenced by coimmunoprecipitations and mass spectrometry, and aggregation of motor proteins dynein and kinesin, along with functional alterations, as reflected by reduced interactions with partner proteins. Prominent homocysteinylation of key neuronal proteins and subsequent aggregation certainly constitute major adverse effects of folate deficiency, affecting normal development with possible long‐lasting consequences.—Akchiche, N., Bossenmeyer‐Pourié, C., Kerek, R., Martin, N., Pourié, G., Koziel, V., Helle, D., Alberto, J.‐M., Ortiou, S., Camadro, J.‐M., Léger, T., Guéant, J.‐L., Daval, J.‐L. Homocysteinylation of neuronal proteins contributes to folate deficiency‐associated alterations of differentiation, vesicular transport, and plasticity in hippocampal neuronal cells. FASEB J. 26, 3980–3992 (2012). www.fasebj.org