ABSTRACT
Conflicting results have been reported concerning the toxicity of cerebrospinal fluid from patients with amyotrophic lateral sclerosis (ALS-CSF) when added to neuronal cultures. The possible toxic factor(s) and the exact mode of action (e.g. requirement of glial cells) have not been identified so far. Glutamate is a potential candidate for this toxic effect, since antagonists of ionotropic glutamate receptors have been shown to attenuate ALS-CSF toxicity. We studied the effects of ALS-CSF on mixed and motoneuron-enriched chick embryonic spinal cord cultures. We found a toxic action of ALS-CSF in both culture types which could not be attenuated by 5 kDa-filtration or 15 min 90 degrees C heating. Nevertheless, the metabotropic glutamate receptor (mGluR) group I antagonist 1-aminoindan-1,5-dicarboxylic acid, but also the group I agonist (s)-3,5-dihydroxyphenylglycine (DHPG) exerted protective effects against ALS-CSF toxicity. In this experimental setting, DHPG may functionally act via a receptor blockade due to sustained activation. No protective effect was seen with the mGluR group III inhibitor (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG). Addition of DHPG did not increase the protective action of the AMPA inhibitor 6-chloro-4-hydroxyquinoline-2-carboxylic acid (6-CKU). Addition of l-glutamate did not mimic these toxic ALS-CSF effects in motoneuron-enriched cultures. Our experiments demonstrate that ALS-CSF toxicity is mediated by a small heat-resistant molecule which may act directly on neurons. Since blockade of group I mGluRs exerts a protective effect, the possibility of targeting these mGluRs pharmacologically in motoneuron disease should be kept in mind.
Subject(s)
Amyotrophic Lateral Sclerosis/cerebrospinal fluid , Cerebrospinal Fluid/drug effects , Excitatory Amino Acid Antagonists/pharmacology , Motor Neurons/metabolism , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Aged , Animals , Cell Count/methods , Cell Death/drug effects , Cell Death/physiology , Cells, Cultured , Cerebrospinal Fluid/chemistry , Cerebrospinal Fluid/metabolism , Chick Embryo , Coculture Techniques/methods , Dose-Response Relationship, Drug , Female , Glutamic Acid/pharmacology , Glycine/analogs & derivatives , Glycine/pharmacology , Humans , Immunohistochemistry/methods , In Situ Nick-End Labeling , Indans/pharmacology , Indoles , Lectins , Male , Middle Aged , Motor Neurons/drug effects , Receptors, Metabotropic Glutamate/physiology , Spinal Cord/cytology , Time FactorsABSTRACT
Glycogenosis type II (Pompe disease) is a lysosomal storage disease caused by deficiency of acid alpha-glucosidase (acid maltase). The disease is autosomal recessive inherited and is clinically and genetically heterogenous. The authors describe a 30-year-old woman affected by late-onset Pompe disease with vascular affection resembling atherosclerotic angiopathy of the elderly. Genetic analysis revealed two novel mutations (Ala237Val and Gly293Arg) in the acid alpha-glucosidase gene in this patient.
