Molecular analysis of homocysteic acid-induced neuronal stress.
Hyperhomocysteinemia is a risk factor for vascular and neuronal lesions often observed with concomitant high levels of homocysteic acid. In contrast to homocysteine, homocysteic acid induces calcium influx into neurons, with characteristics of an excitotoxic glutamatergic agonist at elevated concentrations. On the molecular level this is correlated to fast modifications of proteins (phosphorylation and proteolysis). Within the homocysteic acid induced molecular signature we focused in more detail on phosphorylation of two proteins implicated as risk factors in schizophrenia and neurodegeneration: Dihydropyrimidinase related protein and 14-3-3 protein isoforms. Among the identified proteins there are known chaperones and oxidative metabolism enzymes, but a few are new in context of neuronal stress: Lasp-1, a vitamin D associated factor and an expressed sequence with features of a Rho GDP dissociation inhibitor. Moreover, we detect a specific proteolytic processing of heat shock protein 70 and proteindisulfide isomerase, which is abolished by vitamins (folic acid, vitamin B12, and vitamin B6), which also decrease elevated intracellular calcium levels induced by homocysteic acid.
Sommer
Susanne
S
ProteoSys AG, Carl-Zeiss-Str. 51, 55129 Mainz, Germany.
Hunzinger
Christian
C
Schillo
Simone
S
Klemm
Martina
M
Biefang-Arndt
Katja
K
Schwall
Gerhard
G
Pütter
Sigurd
S
Hoelzer
Kerstin
K
Schroer
Klaus
K
Stegmann
Werner
W
Schrattenholz
André
A
D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020138:Hyperhomocysteinemia / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D020543:Proteome
D020543:Proteome; D006710:Homocysteine; C007956:homocysteic acid; D002118:Calcium