Trace metal profiles characteristic in cultured neurons

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kulkulkan
Posts: 2075
Joined: Tue Mar 13, 2012 1:37 pm

Trace metal profiles characteristic in cultured neurons

Postby kulkulkan » Wed Mar 25, 2015 5:15 pm

Zinc seemed to help in this in-vivo study.

Neural Plast. 2015;2015:985083. doi: 10.1155/2015/985083. Epub 2015 Feb 23.
Effects of trace metal profiles characteristic for autism on synapses in cultured neurons.
Hagmeyer S1, Mangus K1, Boeckers TM2, Grabrucker AM3.
Author information
Abstract
Various recent studies revealed that biometal dyshomeostasis plays a crucial role in the pathogenesis of neurological disorders such as autism spectrum disorders (ASD). Substantial evidence indicates that disrupted neuronal homeostasis of different metal ions such as Fe, Cu, Pb, Hg, Se, and Zn may mediate synaptic dysfunction and impair synapse formation and maturation. Here, we performed in vitro studies investigating the consequences of an imbalance of transition metals on glutamatergic synapses of hippocampal neurons. We analyzed whether an imbalance of any one metal ion alters cell health and synapse numbers. Moreover, we evaluated whether a biometal profile characteristic for ASD patients influences synapse formation, maturation, and composition regarding NMDA receptor subunits and Shank proteins. Our results show that an ASD like biometal profile leads to a reduction of NMDAR (NR/Grin/GluN) subunit 1 and 2a, as well as Shank gene expression along with a reduction of synapse density. Additionally, synaptic protein levels of GluN2a and Shanks are reduced. Although Zn supplementation is able to rescue the aforementioned alterations, Zn deficiency is not solely responsible as causative factor. Thus, we conclude that balancing Zn levels in ASD might be a prime target to normalize synaptic alterations caused by biometal dyshomeostasis.
PMID: 25802764 [PubMed - in process]

kulkulkan
Posts: 2075
Joined: Tue Mar 13, 2012 1:37 pm

Re: Trace metal profiles characteristic in cultured neurons

Postby kulkulkan » Wed Mar 25, 2015 6:04 pm

Zinc deficiency issue may be related to hedgehog activation (also found in ASD).

http://www.ncbi.nlm.nih.gov/pubmed/25787080

J Biol Chem. 2015 Mar 18. pii: jbc.M114.623264. [Epub ahead of print]
Zinc Inhibits Hedgehog Autoprocessing: Linking Zinc Deficiency with Hedgehog Activation.
Xie J1, Owen T2, Xia K1, Singh AV1, Tou E1, Li L1, Arduini B1, Li H3, Wan LQ1, Callahan B2, Wang C4.
Author information
Abstract
Zinc is an essential trace element with wide-ranging biological functions, while the Hedgehog (Hh) signaling pathway plays crucial roles in both development and disease. Here we show that there is a mechanistic link between zinc and Hh signaling. The upstream activator of Hh signaling, the Hh ligand, originates from Hh autoprocessing, which converts the Hh precursor protein to the Hh ligand. In an in vitro Hh autoprocessing assay, we show that zinc inhibits Hh autoprocessing with a Ki of μM. We then demonstrate that zinc inhibits Hh autoprocessing in a cellular environment with experiments in primary rat astrocyte culture. Solution NMR reveals that zinc binds the active site residues of the Hh autoprocessing domain to inhibit autoprocessing, and ITC provided the thermodynamics of the binding. In normal physiology, zinc likely acts as a negative regulator of Hh autoprocessing and inhibits the generation of Hh ligand and Hh signaling. In many diseases, zinc deficiency and elevated level of Hh ligand co-exist, including prostate cancer, lung cancer, ovarian cancer and autism. Our data suggest a causal relationship between zinc deficiency and the overproduction of Hh ligand.

Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
KEYWORDS:
Hedgehog autoprocessing; Hedgehog signaling pathway; cancer; isothermal titration calorimetry (ITC); nuclear magnetic resonance (NMR); zinc
PMID: 25787080 [PubMed - as supplied by publisher] Free full text


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