Research Article: Calcium Signaling and Neurodegeneration

Date Published: April , 2010

Publisher: A.I. Gordeyev

Author(s): I.B. Bezprozvanny.



Neurodegenerative disorders, such as Alzheimer’s disease (AD),
Parkinson’s disease (PD), amyotrophic lateral sclerosis
(ALS), Huntington’s disease (HD), and spinocerebellar
ataxias (SCA) are very important both for fundamental science and for
practical medicine. Despite extensive research into the causes of these diseases, clinical
researchers have had very limited progress and, as of now, there is still no cure for any of
these diseases. One of the main obstacles in the way of creating treatments for these disorders
is the fact that their etiology and pathophysiology still remain unclear. This paper reviews
results that support the so–called “calcium hypothesis of neurodegenerative
diseases.” The calcium hypothesis states that the atrophic and degenerative processes in
the neurons of AD, PD, ALS,
HD, and SCA patients are accompanied by alterations in
calcium homeostasis. Moreover, the calcium hypothesis states that this deregulation of calcium
signaling is one of the early–stage and key processes in the pathogenesis of these
diseases. Based on the results we reviewed, we conclude that the calcium channels and other
proteins involved in the neuronal calcium signaling system are potential drug targets for
AD, PD, ALS, HD, and
SCA therapy.

Partial Text

Calcium signaling in neurons connects membrane excitability with the biological function of
the cell [1]. Since Са2+ channels
are located on the boundary between the “electrical” and the
“signaling” worlds, they play a key role in various aspects of the neuronal
function. Ca2+ signaling is required for short–term and long–term
synaptic plasticity. Because of its extreme importance, neurons use multiple mechanisms to
control intracellular levels of Ca2+, usually within local signaling microdomains.

Neurodenerative disorders, such as Alzheimer’s disease (AD),
Parkinson’s disease (PD), amyotrophic lateral sclerosis
(ALS), Huntington’s disease (HD), and spinocerbellar
ataxias (SCA), are a very important problem both for fundamental science and
for practical medicine. Despite extensive research into the causes of these diseases, clinical
researchers have had very limited progress and as of now there is still no cure for any of
these diseases. Therapeutic drugs used for treating these disorders have only a limited effect,
causing only temporary relief of the symptoms or slowing the disease’s progression (Table 1). A significant advance in the study of these
disorders was achieved with the discovery of mutations that cause the pathological processes.
HD and SCA are genetic disorders, and the genes which cause
these diseases were cloned around 15 years ago (Table
1). Most cases of HD, PD, and ALS are
sporadic, but around 5% of the patients inherit the disorder. Most of the genes which are
involved in the development of the heritable form of the disease have been cloned (Table 1). The study of the genes which cause the
above–mentioned diseases allowed researchers to form a mechanistic hypothesis for the
pathological process and creates a mouse model for studying these pathologies. Most attempts at
studying the above–mentioned pathologies are focused on identifying the main causes of
diseases and developing approaches to affect these causes. For instance, the main cause of
AD was thought to be the formation of amyloid. Because of this, the main
research efforts are directed at preventing the accumulation of amyloid by blocking its
production or facilitating its clearance from the brain. In case of HD, the
main reason is the expression of a mutant form of the huntingtin (Htt)
protein. This means that most experimental efforts are directed at lowering mutant
Htt expression in the brain (such as by using interfering RNA or a antisense

Our neurons are the same age as us. Thus, it is not surprising that the risk of
neurodegenerative diseases increases with age (Table 1).
Comparative studies of neurons from young and old rodents have shown that the neuronal
Са2+–signaling system experiences changes during aging. These data
have been extensively published in the scientific press [2]. Recently, an integral model of age–dependent changes in hypocampal
Ca2+ signaling has been proposed [3]. One of
the main features of aging neurons is an increase in the Ca2+ concentration via
active Ca2+ release from the intracellular depot using InsP3R and RyanR,
an increased release of Ca2+ through the L–type VGCC, an increase of the slow
trace hyperpolarization caused by the activation of Ca2+–dependent K+
channels, a lowered involvement of NMDAR–mediated Ca2+
entrance, and a lowered buffer capacity of the cytosol and activation of calcineurin and
calpains. Such changes in the neuronal Ca2+ dynamics lead to increased sensitivity,
to the induction of long–term depression, and to the increased threshold frequency
required for long–term potentiation in aging neurons [4]. The importance of these changes was also discussed in connection with the
age–dependent disorders of the memory function [4].

Huntigton’s disease (HD) is a genetic disorder which is caused by a
single mutation: the expansion of the CAG (polyglutamine) repeat in the huntingtin
(Htt) gene [5] (Table 1). Medium spiny neurons (MSN) in the striatum are cells
that sustain the most damage during HD. Most researchers agree that the mutant
protein Httexp experiences a “gain of its toxic
function” [6]. The destabilization of neuronal
Ca2+ signaling is one of the toxic functions of the
Httexp protein. Studies of HD patient’s
brains and also model experiments with mice show that the brain experiences sequential changes
in the expression levels of Ca2+–signaling proteins [7]. We proposed the “calcium hypothesis for HD”
[8]. There are several main pathways for the effect of
Httexp on Ca2+ signaling in MSN (Fig. 1). Our laboratory has established that
Httexp directly and specifically binds the C–terminus of
InsP3R1 [9]. The association between
Httexp and InsP3R1 was independently discovered by
random screening [10]. Binding with
Httexp increases the affinity of InsP3R1 for
InsP3 [9]. The key role of InsP3R1
activation in Httexp neurotoxicity was confirmed experimentally in
mouse MSN cultures, which were used to model HD [11, 12], and in genetic
experiments on the Drosophila based HD model [10]. Recent studies show that the viral delivery of a peptide that
destabilizes the interaction between Httexp and InsP3R1
has a protective effect on the striatum MSN in the mouse HD
model both in in vitro and in vivo conditions [13]. These data confirm the importance of increased
InsP3R1 activity in HD pathogenesis. The expression of
Httexp causes increased activity of the NR 2B–bearing
NMDA–receptor [14]. The increased flow through the
NMDA–receptor is a consequence of the effect of Httexp on the
transport of the NMDA–receptor to the plasma membrane [15]. Striatum MSNs expressing Httexp are sensitive
to NMDAR–mediated toxicity. The pharmacological inhibition of the
NMDA–receptor has a neuroprotective effect on a mouse MSN HD–model
culture [11, 16].
Both memantin and riluzole had a neuroprotective effect on MSN cultures with
HD. Memantin was more effective [17].
Memantin also had some positive effects in a small–scale experimental survey of this drug
on HD patients [18], and it will soon
be in the fourth phase of clinical trials for HD therapy (Table 2). Riluzole has completed the third stage of clinical
trials on HD patients, but this study did not turn out to be successful [19] (Table 2).

Like in the case of HD, spinocerbellar ataxias (SCA) are
autosomal dominant genetic disorders caused by the expansion of the polyglutamine sequence in
ataxin proteins (Atx) [5]. There is a number of
observations which indicate that disorders in the neuronal Ca2+ signaling can play a
role in the pathogenesis of these diseases. Some of these data are presented further.

Alzheimer’s disease (AD) is a neurodegenerative disorder which causes
memory loss. In most cases, AD appears sporadically and the first symptoms
emerge in the elderly (after 60). A small fraction of cases (heritable AD
(HAD)) are characterized by the early onset of symptoms and genetic

Sporadic AD is a “multitraget” disorder caused by the synergistic
effect of several pathological factors. One of these factors is aging. The other factors are
determined by the populations of neurons affected by the disease, in this case the cortical and
hypocampal neurons. The main “disease–specific” factor during
AD is probably the accumulation of amyloid. Since AD is a
multitarget disease, the successful therapy must have a complex nature. The population of
neurons which express high levels of Ca2+–binding proteins remain mostly
untouched by AD, while the populations of neurons which express these proteins
at a low level experience extensive damage. A decreased level of Ca2+–binding
proteins is one of the most usual consequences of the natural aging process. Most likely one of
the causes of an increased susceptibility of aged neurons to AD is the
decreased buffer capacity of the neuronal cytosol for Ca2+. Neurons of elderly
patients who suffer from the sporadic form of AD exhibit an activation of
Ca2+–dependent proteases of the calpain family. Calpain activation takes place
as a response to the increased levels of Ca2+ in the cytosol. Activated calpains
cleave various proteins which are required for the normal functioning of the neuron, which
results in neuronal dysfunction and apoptosis.

The calcium hypothesis of AD pathogenesis. The central idea for
explaining AD pathology is currently the amyloid hypothesis, which states that
the main reason for neuron death and the decreased number of synapses during this disorder is
the increased production of Aβ42 amyloid peptide (or the increased Aβ42/40 ratio)

Mitochondrial stabilizers and antidepressants. Ketasyn, Creatine, coenzyme Q10
(CoQ10), and MitoQ have all passed clinical trials for the therapy of AD and
HD. Since mitochondria play a key role in the pathogenesis of these diseases
[70], these clinical trials were expected to yield some
positive results. However, mitochondria are involved in the pathological process at a
relatively late stage, so the effect of these drugs can be expected to be limited. In fact,
according to reports on this type of drugs, only modest therapeutic effects have been reported
in the treatment of neurodegenerative disorders [70].