ISSN 1022-7954, Russian Journal of Genetics, 2006, Vol. 42, No. 1, pp. 89–93. © Pleiades Publishing, Inc., 2006.
Original Russian Text © A.L. Zherebtsova, M.I. Shadrina, E.V. Semenova, G.N. Levitsky, A.V. Alekhin, P.A. Slominsky, V.I. Skvortsova, S.A. Limborska, 2006, published in Gene-
tika, 2006, Vol. 42, No. 1, pp. 104–109.
Motor neuron disease (MND) is a group of chronic,
clinically heterogeneous fatal pathologies, the patho-
genesis of which has not been determined conclusively.
They are characterized by selective damage to upper
and/or lower motor neurons. In most cases (90%), the
disease is sporadic. Familial forms are also known (5–
10%). The clinical signs of the sporadic and familial
forms of MND are identical .
Several hypothetical etiological and pathogenetic
mechanisms of this disease are the most plausible. To
date, several aspects of MND pathogenesis have been
studied in Russian patients with conﬁrmed diagnosis of
MND. Mutations in several genetic systems have been
found to be involved; they may mediate the develop-
ment of oxidative stress (
disturbance in the xenobiotic detoxiﬁcation system
), changes in the neuron
cytoskeleton, and disturbance of axonal transport
), which, apparently, leads to MND [2–7].
Two universal mechanisms, oxidative stress and
excitotoxicity, which may induce neuron necrosis or
apoptosis, are known to be involved in the damage of
nerve cells in diseases with various etiologies [8–15].
Excitotoxicity begins with excessive release of excita-
tory neurotransmitters into the synaptic gap. This leads
to the hyperactivation of postsynaptic glutamate recep-
tors, which disturbs the permeability of ion channels.
Excessive accumulation of intracellular calcium trig-
gers a cascade of reactions, including the activation of
proteolytic enzymes and destruction of cellular struc-
tures, and leads to an increase in nitrogen oxide synthe-
sis and lipid peroxidation, resulting in oxidative stress,
disturbance in the synthesis of neurotrophic factors,
and programmed cell death (apoptosis).
The glutamatergic system plays an important role in
the functioning of the human central nervous system,
and its functional disturbance is a possible cause of
neurodegenerative diseases. Glutamate is the main neu-
rotransmitter of this system; in addition to fulﬁlling its
main function (neurotransmission), this amino acid
may sometimes act as a potent neurotoxin, causing or
exacerbating neuron damage and harming the brain
because of the excitotoxic effect .
To date, much evidence has been accumulated for an
important role of glutamate excitotoxicity in the neuro-
degeneration contributing to MND [8, 9, 11, 16, 17].
The glutamate concentration is signiﬁcantly increased
in the cerebrospinal ﬂuid and blood and signiﬁcantly
decreased in all regions of the brain and spinal cord
studied in MND patients. The increased amount of
glutamate in the synaptic gap is assumed to result from
an enhanced presynaptic discharge, disturbed active
uptake and transport, astroglial pool blockage, and
changes in the functional activity of glutamate recep-
Increased glutamate levels may induce neurotoxic-
ity associated with many pathological processes.
Therefore, glutamate transport is an important mecha-
nism for maintaining low extracellular concentrations
of this neurotransmitter, which promotes synaptic sig-
naling and restricts the possible neurotoxicity resulting
from the excitotoxic effect of glutamate .
Analysis of the Possible Involvement of the Glutamate
and the Glutamate Receptor Genes
in the Pathogenesis of Motor Neuron Disease
in the Russian Population
A. L. Zherebtsova
, M. I. Shadrina
, E. V. Semenova
, G. N. Levitsky
, A. V. Alekhin
P. A. Slominsky
, V. I. Skvortsova
, and S. A. Limborska
Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, 123182 Russia;
fax: (495) 196-02-21; e-mail: firstname.lastname@example.org
Russian State Medical University, Moscow, 129327 Russia
Received May 13, 2005
—Polymorphisms of the genes of the glutamatergic system
analyzed in patients with sporadic motor neuron disease (MND) from Russia. The disease is not associated with
polymorphic alleles of the genes studied, which indicates that
play an insigniﬁcant
role in the pathogenesis of sporadic MND.