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Glutaric Acid Neurotoxicity: Mechanisms and Actions

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Handbook of Neurotoxicity

Abstract

Glutaric acid (GA) is found in high concentrations in glutaric acidemia type 1 (GA 1), an inherited neurometabolic disorder of intoxication characterized by acute striatal degeneration, progressive extrastriatal abnormalities, white matter changes, and cerebral atrophy. Untreated GA 1 patients present increased mortality and manifest with a severe complex movement disorder due to striatum injury. Mounting evidence indicates that GA has a central role in the brain damage of GA 1, by disturbing essential processes necessary for cerebral development and functioning. This chapter will update the current knowledge on GA neurotoxic effects, which were mainly obtained from animal studies. GA disrupts neurotransmission, redox homeostasis, bioenergetics, blood-brain barrier, brain vasculature, and myelination, besides inducing reactive astrogliosis and neuronal death. In addition, GA in vivo administration to rats provokes neurodevelopmental motor delay, cognitive impairment, and convulsions. Studies performed in humans support most of the animal data relative to GA-induced neurotoxic effects. Potential novel therapies targeting the deleterious effects of GA to improve the outcome of GA 1 patients will also be discussed.

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Abbreviations

3HGA:

3-Hydroxyglutaric acid

AMPA:

α-Amino-3-hydroxy-5-methylisoxazole propionic acid

BBB:

Blood-brain barrier

C5DC:

Glutarylcarnitine

CA:

Citric acid cycle

CK:

Creatine kinase

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

ER:

Endoplasmic reticulum

ETF:

Electron transfer flavoprotein

ETFDH:

Mitochondrial electron transfer flavoprotein dehydrogenase

FAD:

Flavin adenine dinucleotide

GA 1:

Glutaric acidemia type 1

GA 2:

Glutaric acidemia type 2

GA 3:

Glutaric acidemia type 3

GA:

Glutaric acid

GABA:

γ-Aminobutyric acid

GCDH:

Glutaryl-CoA dehydrogenase

Gcdh-/-:

Glutaryl-CoA dehydrogenase deficient mice

GDH:

Glutamate dehydrogenase

GFAP:

Glial fibrillary acidic protein

GPx:

Glutathione peroxidase

GSH:

Reduced glutathione

HGMD:

Human Gene Mutation Database

IL:

Interleukin

Lys:

L-Lysine

MDA:

Malondialdehyde

Mit-CK:

Mitochondrial creatine kinase

NaC3:

Sodium dicarboxylate cotransporter 3

NMDA:

N-Methyl-D-aspartic acid

OAT:

Organic anion transporter

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SUGCT:

Succinate-hydroxymethylglutarate CoA-transferase

TNF-α:

Tumor necrosis factor-alpha

VEGF:

Vascular endothelial growth factor

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Authors and Affiliations

  1. Department of Biological Sciences, Integrated Regional University of High Uruguay and Missions, Erechim, RS, Brazil

    Alexandre U. Amaral

  2. Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    Gustavo C. Ferreira

  3. Department of Biochemistry, Institute of Basic Sciences and Health, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil

    Bianca Seminotti, Guilhian Leipnitz & Moacir Wajner

  4. Medical Genetics Service, Clinical Hospital of Porto Alegre, Porto Alegre, RS, Brazil

    Moacir Wajner

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  1. Alexandre U. Amaral
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  2. Gustavo C. Ferreira
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  3. Bianca Seminotti
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  4. Guilhian Leipnitz
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  5. Moacir Wajner
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Correspondence to Moacir Wajner .

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  1. Department of Biomedical Sciences, East Tennessee State University, Johnson City, TN, USA

    Richard M. Kostrzewa

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Amaral, A.U., Ferreira, G.C., Seminotti, B., Leipnitz, G., Wajner, M. (2021). Glutaric Acid Neurotoxicity: Mechanisms and Actions. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-030-71519-9_186-1

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