new_details_on_formaldehyde

NEW DETAILS ON HOW FORMALDEHYDE AND FORMIC ACID FROM METHANOL ARE NEUROTOXIC

Compiled By Rich Murray, MA
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Posted: 04 September 2007

Subject: New Details On How Formaldehyde And Formic Acid From Methanol Are Neurotoxic: Chun Lai Nie , Rong Giao He, et al, PLoS ONE 2(7): e629 2007.07.18 Chinese Academy of Sciences, Beijing: Murray 20097.09.01

New details on how formaldehyde and formic acid from methanol are neurotoxic: Chun Lai Nie, Rong Giao He, et al, PLoS ONE 2(7): e629 2007.07.18 Chinese Academy of Sciences, Beijing: Murray 20097.09.0 http://groups.yahoo.com/group/aspartameNM/message/1470

"Recent studies have shown that neurodegeneration is closely related to misfolding and aggregation of neuronal tau."

"The significant protein tau aggregation induced by formaldehyde and the severe toxicity of the aggregated tau to neural cells may suggest that toxicity of methanol and formaldehyde ingestion is related to tau misfolding and aggregation."

"Neuronal tau is an important protein in promoting and stabilizing the microtubule system involved in cellular transport and neuronal morphogenesis."

"Both formaldehyde and acetaldehyde can go through the blood-brain barrier and cause some lesions to CNS, especially our visual system [38].

Clinically, the lethal dose of formaldehyde for human beings is about 0.08% in the circulation [39].

We have shown in the present study that formaldehyde can significantly induce tau aggregation and polymerization at concentrations even lower than 0.08%, the clinical dose of toxicosis."

"Formaldehyde exposure leads to formation of DNA/protein crosslinks, a major mechanism of DNA damage.

The DNA/protein crosslinks have been used as a measure of dose in drug delivery [20].

Formaldehyde, as a crosslinking agent, also reacts with thiol and amino groups, leading to protein polymerization [21], [22].

Furthermore, methanol ingestion is an important public health concern because of the selective actions of its toxic metabolites, formaldehyde and formic acid, on the retina, the optic nerves and the central nervous system (CNS) [23].

Illicit consumption of industrial methylated spirits can cause severe and even fatal illness [24].

In the liver and retina, methanol is oxidized by alcohol dehydrogenase, resulting in formaldehyde.

In semicarbazide-sensitive amine oxidase (SSAO)-mediated pathogenesis of Alzheimer's disease, formaldehyde interacts with -amyloids and produces irreversibly cross-linked neurotoxic amyloid-like complexes [21], [22], [25].

We have examined the role of formaldehyde in misfolding of protein tau [26].

In particular, we investigated the toxicity of formaldehyde-induced tau aggregates on human neuroblastoma cells (SH-SY5Y cell line) and rat hippocampal cells [27].

The results showed that low concentrations (0.01-0.1%) of formaldehyde are sufficient to induce formation of amyloid-like tau aggregates, which can induce apoptosis of both SH-SY5Y and hippocampal cells.

This may be significant to understand the mechanism of chronic damage caused by methanol toxicity and formaldehyde stress [18], [28].

However, we have still not known the mechanism of protein tau aggregation in the presence of formaldehyde at low concentrations.

The present study concerns the characteristic of misfolding and polymerization of extracellular and intracellular neuronal tau induced by formaldehyde at low concentrations."

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Formaldehyde at Low Concentration Induces Protein Tau into Globular Amyloid-Like Aggregates In Vitro and In Vivo
Chun Lai Nie 1,
Yan Wei 1,
Xinyong Chen 2,
Yan Ying Liu 1,
Wen Dui 1,
Ying Liu 1,
Martyn C. Davies 2, Martyn.Davies@nottingham.ac.uk,
Saul J.B. Tendler 2, Saul.Tendler@nottingham.ac.uk,
Rong Giao He 1* herq@sun5.ibp.ac.cn,
1 State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Graduate School, Chinese Academy of Sciences, Chaoyang District, Beijing, China, 2 Laboratory of Biophysics and Surface Analysis, School of Pharmacy, The University of Nottingham, Nottingham, United Kingdom

Abstract

Recent studies have shown that neurodegeneration is closely related to misfolding and aggregation of neuronal tau.

Our previous results show that neuronal tau aggregates in formaldehyde solution and that aggregated tau induces apoptosis of SH-SY5Y and hippocampal cells.

In the present study, based on atomic force microscopy (AFM) observation, we have found that formaldehyde at low concentrations induces tau polymerization whilst acetaldehyde does not.

Neuronal tau misfolds and aggregates into globular-like polymers in 0.01-0.1% formaldehyde solutions.Apart from globular-like aggregation, no fibril-like polymerization was observed when the protein was incubated with formaldehyde for 15 days.

SDS-PAGE results also exhibit tau polymerizing in the presence of formaldehyde.

Under the same experimental conditions, polymerization of bovine serum albumin (BSA) or -synuclein was not markedly detected.

Kinetic study shows that tau significantly misfolds and polymerizes in 60 minutes in 0.1% formaldehyde solution.

However, presence of 10% methanol prevents protein tau from polymerization.

This suggests that formaldehyde polymerization is involved in tau aggregation.

Such aggregation process is probably linked to the tau's special "worm-like" structure, which leaves the -amino groups of Lys and thiol groups of Cys exposed to the exterior.

Such a structure can easily bond to formaldehyde molecules in vitro and in vivo.

Polymerizing of formaldehyde itself results in aggregation of protein tau.

Immunocytochemistry and thioflavin S staining of both endogenous and exogenous tau in the presence of formaldehyde at low concentrations in the cell culture have shown that formaldehyde can induce tau into amyloid-like aggregates in vivo during apoptosis.

The significant protein tau aggregation induced by formaldehyde and the severe toxicity of the aggregated tau to neural cells may suggest that toxicity of methanol and formaldehyde ingestion is related to tau misfolding and aggregation.

Funding: This project was supported by NSFB (06J11), the NSFC (Nos. 90206041, 30570536 and 30621004) and 973-Project (2006CB500703 and 2006CB911003).

Competing interests: The authors have declared that no competing interests exist.

Academic Editor: Christophe Herman, Baylor College of Medicine, United States of America

Citation: Nie CL, Wei Y, Chen X, Liu YY, Dui W, et al. (2007) Formaldehyde at Low Concentration Induces Protein Tau into Globular Amyloid-Like Aggregates In Vitro and In Vivo. PLoS ONE 2(7): e629. doi:10.1371/journal.pone.0000629

Received: March 5, 2007; Accepted: June 13, 2007; Published: July 18, 2007

Copyright: (c) 2007 Nie et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* To whom correspondence should be addressed. E-mail: herq@sun5.ibp.ac.cn

Introduction

Neuronal tau is an important protein in promoting and stabilizing the microtubule system involved in cellular transport and neuronal morphogenesis. The tau molecule can be subdivided into an amino-terminal domain that projects from the microtubule surface and a carboxy-terminal microtubule-binding domain.The discovery that incubation of bacterially expressed human tau with sulphated glycosaminoglycans leads to bulk assembly of tau filaments [1], making it possible to obtain structural information [2]. By using circular dichroism measurement, Schweer et al. have found that protein tau lacks secondary structures and is considered in a "worm-like" conformation with a high flexibility [3]. Therefore, the side-chains of amino acids such as Lys, Cys, Thr and Ser are mostly exposed and vulnerable to chemical modification.

Recently, many laboratories have found that misfolding and aggregation of protein tau are involved in neurodegeneration [2], [4]-[6].Protein tau has been found as the major component of paired helical filaments in neurofibrillary tangles in the brains of Alzheimer's patients, where abnormal hyper-phosphorylation induces tau to misfold and form the paired helical filaments, depositing in the cytoplasm of neurons [7]-[10]. Recently, a great deal of evidence has demonstrated that oxidation and glycation stresses are key causal factors of neuronal degenerative diseases [11]-[13]. Both of them inevitably produce a variety of unsaturated carbonyls as intermediates, like malondialdehyde and 4-hydroxynonenal, which usually cause carbonyl-amino crosslinking and lead to accumulation of irreversible changes (like lipofuscin) related to various neurodegenerative diseases in particular [14]-[16]. Such carbonyl stress-related reactions (carbonylation) can form unstable and reversible 1:1 amino-carbonyl (Shiff's base) compounds at an early stage of protein modification [16], [17]. Carbonylation binds and blocks -/ - amino groups, and results in changes in charge and conformation of a protein.

In order to investigate the relationship between carbonylation and protein tau misfolding, the basic and simplest carbonyl compound formaldehyde [18] has come into our attentions.

Formaldehyde is a common environmental agent found in paint, cloth, exhaust gas and many other medicinal and industrial products [19].

Formaldehyde exposure leads to formation of DNA/protein crosslinks, a major mechanism of DNA damage.