Mild guanidinoacetate increase under partial guanidinoacetate methyltransferase deficiency strongly affects brain cell development.

Details

Ressource 1Download: BIB_294E3C88D1F4.P001.pdf (1690.32 [Ko])
State: Public
Version: Author's accepted manuscript
Serval ID
serval:BIB_294E3C88D1F4
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mild guanidinoacetate increase under partial guanidinoacetate methyltransferase deficiency strongly affects brain cell development.
Journal
Neurobiology of Disease
Author(s)
Hanna-El-Daher L., Béard E., Henry H., Tenenbaum L., Braissant O.
ISSN
1095-953X (Electronic)
ISSN-L
0969-9961
Publication state
Published
Issued date
2015
Peer-reviewed
Oui
Volume
79
Pages
14-27
Language
english
Abstract
Among cerebral creatine deficiency syndromes, guanidinoacetate methyltransferase (GAMT) deficiency can present the most severe symptoms, and is characterized by neurocognitive dysfunction due to creatine deficiency and accumulation of guanidinoacetate in the brain. So far, every patient was found with negligible GAMT activity. However, GAMT deficiency is thought under-diagnosed, in particular due to unforeseen mutations allowing sufficient residual activity avoiding creatine deficiency, but enough guanidinoacetate accumulation to be toxic. With poorly known GAA-specific neuropathological mechanisms, we developed an RNAi-induced partial GAMT deficiency in organotypic rat brain cell cultures. As expected, the 85% decrease of GAMT protein was insufficient to cause creatine deficiency, but generated guanidinoacetate accumulation causing axonal hypersprouting and decrease in natural apoptosis, followed by induction of non-apoptotic cell death. Specific guanidinoacetate-induced effects were completely prevented by creatine co-treatment. We show that guanidinoacetate accumulation without creatine deficiency is sufficient to affect CNS development, and suggest that additional partial GAMT deficiencies, which may not show the classical brain creatine deficiency, may be discovered through guanidinoacetate measurement.
Pubmed
Web of science
Open Access
Yes
Create date
06/07/2015 13:31
Last modification date
20/08/2019 13:09
Usage data