The Cerebellum

, Volume 11, Issue 3, pp 630–639 | Cite as

Deranged Calcium Signaling in Purkinje Cells and Pathogenesis in Spinocerebellar Ataxia 2 (SCA2) and Other Ataxias

Article

Abstract

Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of more than 30 autosomal-dominant genetic and neurodegenerative disorders. SCAs are generally characterized by progressive ataxia and cerebellar atrophy. Although all SCA patients present with the phenotypic overlap of cerebellar atrophy and ataxia, 17 different gene loci have so far been implicated as culprits in these SCAs. It is not currently understood how mutations in these 17 proteins lead to the cerebellar atrophy and ataxia. Several pathogenic mechanisms have been studied in SCAs but there is yet to be a promising target for successful treatment of SCAs. Emerging research suggests that a fundamental cellular signaling pathway is disrupted by a majority of these mutated genes, which could explain the characteristic death of Purkinje cells, cerebellar atrophy, and ataxia that occur in many SCAs. We propose that mutations in SCA genes cause disruptions in multiple cellular pathways but the characteristic SCA pathogenesis does not begin until calcium signaling pathways are disrupted in cerebellar Purkinje cells either as a result of an excitotoxic increase or a compensatory suppression of calcium signaling. We argue that disruptions in Purkinje cell calcium signaling lead to initial cerebellar dysfunction and ataxic sympoms and eventually proceed to Purkinje cell death. Here, we discuss a calcium hypothesis of Purkinje cell neurodegeneration in SCAs by primarily focusing on an example of spinocerebellar ataxia 2 (SCA2). We will also present evidence linking deranged calcium signaling to the pathogenesis of other SCAs (SCA1, 3, 5, 6, 14, 15/16) that lead to significant Purkinje cell dysfunction and loss in patients.

Keywords

Purkinje cell Calcium Ataxia Polyglutamine Excitotoxicity Neurodegeneration SCA2 

Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of autosomal-dominant genetic and neurodegenerative disorders. SCAs are generally characterized by cerebellar atrophy and a progressive incoordination of movement known as ataxia [1, 2, 3]. Over 30 SCAs have been identified and named in the chronological order of their discovery from SCA1 to SCA30 [4]. Although all SCA patients present with the phenotypic overlap of cerebellar atrophy and ataxia, other brain regions are differentially affected in each SCA. Seventeen genes have been associated with these SCAs and it is not understood how mutations in those SCA-associated genes lead to the SCA pathogenesis [5]. The pathogenesis of SCAs is not fully understood, however, several different pathogenic mechanisms have been studied in SCAs such as dysregulation of transcription and gene expression, alterations in calcium homeostasis and synaptic neurotransmission, mitochondrial stress and apoptosis (reviewed in [4, 6, 7]). Currently, therapy for SCA patients is mainly supportive and directed at treating individual symptoms in each [7, 8]. No disease modifying therapy exists for any of the SCAs. In order to develop a successful treatment of SCAs, it will be important that a valid therapeutic target and the pathogenic pathways are identified.

Emerging research suggest that a fundamental cellular pathway is disrupted by some of the mutated SCA genes, which could explain the characteristic death of Purkinje cells, cerebellar atrophy and the resulting ataxia [9, 10, 11, 12, 13, 14, 15, 16, 17]. We propose that mutations in SCA genes disrupt multiple cellular pathways but SCA pathogenesis does not begin and progress until calcium homeostasis is disrupted in cerebellar Purkinje cells. This can occur either as a result of an excitotoxic increase or a compensatory suppression of calcium signaling, which eventually leads to cellular dysfunction and cell death. Similar hypothesis has been recently proposed based on the comparison of genes involved in cerebellar plasticity and human ataxias [18]. Calcium signaling in Purkinje cells is important for normal cellular function as these neurons express a variety of calcium channels, calcium-sensitive kinases and phosphatases, calcium sensors, and calcium buffers to tightly maintain calcium homeostasis. Glutamate, an excitatory neurotransmitter, induces a transient increase in the cytoplasmic calcium levels of PCs via activating ionotropic α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors and metabotropic glutamate receptors (mGluR). Activation of AMPA receptors causes membane depolarization, activation of voltage-gated calcium channels and calcium Ca2+ influx into the cytoplasm. Activation of mGluR causes Ca2+ release from endoplasmic reticulum stores via activating inositol 1,4,5-triphosphate receptors (ITPR) to allow a transient increase in cytoplasmic Ca2+ levels. Initial Ca2+ signals further amplified by Ca2+-induced Ca2+ release mechanism (CICR) which involves activation of ryanodine receptors (RyanR), an intracellular Ca2+ release channels. When tightly controlled, a transient change in calcium levels functions as an intracellular messenger important for gene transcription [19] and synaptic neurotransmission [20]. Aberrant calcium levels can uncouple neuronal plasticity and activate toxic cascades leading to cell death. Several studies have implicated deranged calcium signaling in neurodegenerative disorders culminating in the “calcium hypothesis of neurodegeneration”. This hypothesis posits that as fundamental as calcium levels are to cellular functions, dysregulation of calcium homeostasis is detrimental to neuronal survival [21].

Purkinje cells (PCs) are the only efferent projection from the cerebellar cortex. They modulate the activity of neurons in the deep cerebellar nuclei (DCN) via inhibitory signals; hence PC dysfunction and death in SCAs would lead to cerebellar dysfunction. Without inhibition from PCs, DCN neurons will become hyper-excitable, motor centers receiving DCN input will be affected and incoordination of movement will be the outcome [22]. This explains why PCs are suspected to be the likely site of onset of SCA pathogenesis. They are very sensitive to cellular changes [23], and over 75% of PC are reported to be lost in a number of the SCAs (Table 1) [2]. In this review, we will discuss the calcium hypothesis of PCs neurodegeneration outlining recent work focused on studies of the mechanisms underlying SCA2 pathogenesis. We will also discuss how deranged calcium signaling could be playing a role in the pathogenesis of other SCAs that present with significant PC dysfunction and loss such as the case for SCA1, 3, 5, 6, 14, 15/16 patients.
Table 1

Features of spinocerebellar ataxias linked with abnormal Ca2+ signaling

Disease subtype

Locus

Protein

Mutation

Normal repeats

SCA patient repeats

Pathology

Effect on calcium signaling

SCAl

6p

Ataxin 1

PolyQ exp

6-39

39-82

>75% PC loss

Increase

SCA2

12q

Ataxin 2

PolyQ exp

14-31

33-64

>75% PC loss

Increase

SCA3

14q

Ataxin 3

PolyQ exp

12-42

52-86

<25% PC loss

Increase

SCA5

11q

β-III spectrin

Non-repeat mutations & deletions

N/A

N/A

No data

Increase

SCA6

19p

CACNA1A

PolyQ exp

4-18

19-30

>75% PC loss

Increase/Decrease

SCA14

19q

PKCγ

Non-repeat mutations

N/A

N/A

No data

Increase/Decrease

SCA15/16

3p

ITPR1

Non-repeat deletions or mutations

N/A

N/A

No data

Decrease

Number of repeats adapted from [5]. SCA pathology adapted from [2]

PolyQ exp polyglutamine expansion, N/A not applicable

Deranged Calcium Signaling in SCA2

SCA2 patients suffer from a progressive cerebellar syndrome with ataxia of gait and stance, ataxia of limb movements, and dysarthria [1, 2, 3]. The SCA2 is caused by an expansion and translation of unstable CAG repeats in the gene encoding ataxin-2 from the normal 22 to more than 31 extra glutamine repeats [24, 25, 26]. The pathogenesis of SCA2 is currently not understood. Polyglutamine-expanded ataxin-2 (ATXN2exp) protein, similar to wildtype ataxin-2 (ATXNwt), has a wide spread expression. No severe aggregation of ATXN2exp or formation of inclusion bodies was observed in studies of brain samples from SCA2 patients [27]. The cerebellar PCs are preferentially lost in SCA2 patients (Table 1) [2]. Genetic knockouts of ATXN2 orthologs in fly and worm resulted in embryonic lethality [28, 29]. ATXN2 knockout mice were viable but displayed a late-onset obesity phenotype [30]. Mice deficient in ATXN2 did not show Purkinje cell loss or marked changes in the Purkinje cell dendritic tree [30]. Non-essential role of ATXN2 in rodents is most likely related to the presence of orthologs and redundancy in its function [30]. Thus, the polyglutamine expansion in ataxin-2 likely does not cause a loss of function nor a dominant negative effect but a gain of toxic function [30]. The role of calcium signaling in the pathogenesis of SCA2 is supported by the genetic association between polymorphisms in the CACNA1A gene and the age of disease onset in patients diagnosed with SCA2. The CACNA1A gene encodes the pore-forming α1A subunit of CaV2.1, a P/Q-type voltage-gated calcium channel. Patients with a prematurely early age of onset of SCA2 tended to have a longer CAG-repeat length in the CACNA1A gene [31]. Longer CAG-repeat lengths in this gene have been genetically linked to SCA6.

The role of aberrant neuronal calcium signaling in SCA2 pathogenesis was strengthened further by a finding in our laboratory that ATXN2exp but not ATXN2wt specifically binds type 1 inositol (1,4,5) triphosphate receptors (ITPR1s) [17]. This suggested that its association would result in either a sensitization or desensitization of ITPR1s to activation by inositol 1,4,5-triphosphate (InsP3) during glutamate signaling in PCs. PCs express extremely high levels of intracellular ITPR1 [32, 33], which are present on endoplasmic reticulum (ER) membranes. ATXN2exp and ATXN2wt were found to localize and associate with ER membranes [34]. In a lipid bilayer reconstitution experiments, we examined the effect of ATXN2exp expression on ITPR1 activation in single channel recordings of ITPR1s co-expressed with ATXN2exp. We found that the presence of ATXN2exp but not ATXN2wt substantially sensitized ITPR1s to activation by InsP3 in bilayers [17].

To test the importance of Ca2+ signaling in SCA2 pathogenesis we performed a series of experiments in a SCA2 transgenic mouse model (SCA2-58Q, generated by [27]) expressing 58 glutamine repeats (ATXN2exp) in the ataxin-2 gene under the control of the L7/Pcp2 PC-specific promoter. These mice exhibit behavioral deficits, loss of Purkinje cell dendritic arborization and Purkinje cell death, which is progressive and akin to SCA2 patient pathology [27]. We found that there was a significant increase in calcium release from ER stores via ITPR1s in calcium imaging experiments in primary PCs cultured from SCA2-58Q transgenic mice, which was not observed in PCs cultured from wildtype littermates [17]. When ryanodine or dantrolene were added to block ryanodine receptors and ER calcium release in PC cultures, the effect of ATXN2exp expression was reversed as ER calcium release returned to the wildtype levels [17]. In a TUNEL assay of PC death, we found that the addition of dantrolene to block the excessive ER calcium release caused by ATXN2exp expression attenuated exogenous glutamate-induced PC death [17]. Furthermore, long-term feeding of SCA2-58Q mice with a calcium stabilizer dantrolene alleviated the age-dependent motor coordination deficits in these mice quantified by rotarod and beam-walk behavioral assays [17]. Stereological counting of PCs showed a rescue of PC death in 12-month-old SCA2-58Q mice fed with dantrolene [17]. The above lines of evidence supported the hypothesis that deranged calcium signaling plays an important role in SCA2 pathogenesis.

Supranormal Calcium Signaling and Purkinje Cell Dysfunction in SCA2

The exact pathway(s) that is activated by excitotoxic calcium signaling and that causes PC degeneration in SCA is unknown. We propose that in Purkinje cells in SCA2 animals and patients, the significant increase in calcium release from the ER into the cytoplasm becomes toxic and initiates cell death via multiple pathways (Fig. 1) [7, 17]. A transient increase in cytoplasmic calcium levels can be tolerated by cells and is important for many neuronal processes but if prolonged can be detrimental. We suggest that excessive cytosolic calcium is first taken up by the PC calcium buffers, calbindin (CB) and parvalbumin (PV), which is the first line of defense against calcium overload (Fig. 1) [35]. The important neuroprotective role of these endogenous Ca2+ buffers is supported by the fact that although CB knockout or PV knockout mice are only slightly ataxic [36, 37], the double knockout CB−/−PV−/− mice display severe ataxic phenotype and alterations in PC morphology [38].
Fig. 1.

Calcium hypothesis of SCA2 pathogenesis. We propose that the ITPR1-ATXN2exp association results in increased ITPR1 activity leading to deranged neuronal calcium signaling. The abnormal cytosolic calcium levels result in mitochondrial Ca2+ overload, release of cytochrome c and induction of PC cell death via dark cell degeneration (DCD). In addition, abnormal Ca2+ signals also affect LTD mechanisms, leading to uncoupling of synaptic plasticity mechanisms in SCA2 PC cells from intracellular Ca2+ signaling

Some of the excess released calcium is also taken up by mitochondria [39], which can become overloaded as well, eventually creating free radicals and inducing oxidative stress, activating apoptotic cascades and necrotic cell death [21, 40] (Fig. 1). Excessive cytoplasmic calcium also leads to excitotoxic glutamate release which can cause reactive oxygen species production and damage DNA [41]. Intracellular calcium levels higher than physiological concentrations can also cause an increase in activation of multiple calcium-sensitive enzymes. These include calcium-sensitive phosphatases and kinases that alter gene transcription upon activation [19], as well as proteases such as calpains, which upon activation cause degradation of cellular substrates [42]. Excessive activation of nitric oxide synthase also abnormally increases intracellular nitric oxide levels and causes DNA and mitochondrial damage [43]. In the absence of sufficient intracellular calcium buffering, calcium-induced excitotoxicity is detrimental to cell survival.

We argue that the uncontrolled calcium burden could then fall on cerebellar plasticity mechanisms to attempt to control. Indeed, it has been suggested that cerebellar LTD could instead or in addition to playing a role in motor learning also play a role in neuroprotection in PCs [18]. Cerebellar LTD is triggered in response to an increase in intracellular calcium following stimulation at both parallel and climber fiber synapses [44, 45, 46, 47]. This coincident and transient rise in calcium could function in coding information, supporting the idea that LTD is involved in motor learning [48, 49]. However, in instances of supranormal calcium signaling, LTD could also function to suppress synaptic transmission and to prevent overexcitation. Accordingly, it has been reported that blocking glutamate uptake and increasing synaptic glutamate levels increases the induction of LTD in cerebellar slices [50], suggesting that LTD could protect PCs from detrimental effects of excitotoxic synaptic transmission. This idea that cerebellar LTD could play a separate role from motor learning in the cerebellum is supported also by evidence showing that LTD can be disrupted without affecting motor learning in two types of motor tasks [51, 52]. Therefore, we propose that LTD could be a mechanism that PC cells use to relieve themselves from excitotoxicity by suppressing glutamatergic synaptic transmission when intracellular calcium exceeds a safe threshold. Although meant to be protective, this “super LTD” may also be linked with early manifestation of ataxic phenotype (Fig. 1). This is because increase in LTD supresses activity of PC cells and removes inhibition of postsynaptic DCN neurons. As a result, hyper-excitability and ataxia symptoms can occur [22].

The proposed hypothesis predicts that LTD is abnormal in PCs of SCA2 mice. ITPR1s, which are required for calcium release from intracellular stores in the induction of cerebellar LTD [45, 46, 53], are excessively sensitized to activation by InsP sub(3) in PCs of SCA2 mice [17]. Consequently, in PCs of SCA2 mice, when there is a calcium overload resulting from the sensitization of ITPR1s to activation by InsP3, it is possible that this overwhelms and uncouples synaptic plasticity mechanisms that require specific and transient changes in intracellular calcium levels. This can be tested by comparing LTD induction in cerebellar slices from SCA2 and wild type mice. These studies, currently in progress in our laboratory, may also provide novel insights into cerebellar plasticity in normal and pathophysiological situations.

Purkinje Cells in SCA2-58Q Mice Die by Dark Cell Degeneration

Although a dysfunction in cerebellar LTD may be responsible for initial symptoms of SCA2, it is likely that the degeneration and eventual death of PCs are responsible for the symptoms of the disease in the late stages. What is a mode of PC cell death in SCA2? In our previous studies, we demonstrated that application of glutamate induces apoptotic cell death of SCA2-58Q PC neurons in in vitro culture which can be detected by TUNEL staining [17]. What is a mode of cell death of PC cells in vivo? A number of previous studies described a characteristic mode of excitotoxic cell death of PC neurons which has been termed dark cell degeneration (DCD). DCD has been reported in PCs resulting from excitotoxicity in the form of excessive presynaptic glutamate stimulation or sensitivity to glutamate in the synapse [54, 55, 56]. It is suggested to lie in a spectrum between classical apoptotic and passive necrotic cell death because it shares characteristics with both forms of death [55]. DCD mode of PC cell death has been previously identified in mouse models of SCA7 and SCA28 suggesting that excitotoxicity could be central for pathogenesis of these disorders [56, 57]. DCD in SCA7 PCs is induced by the absence of Bergmann glia, which ensheath PCs and re-uptake glutamate from synapses [57]. In SCA28, DCD appears to be mitochondria-mediated [56].

Typically DCD is evaluated by the analysis of transmission electron microscopy (TEM) images of cerebellar sections. The rationale behind this method is that unlike healthy PCs, as unhealthy PCs degenerate as a result of excitotoxity-induced cell death cascades, the cytoplasm fills with cellular aggregates and debris. The compounds used for TEM processing form an extensive complex that bind to cellular protein structures. Once processed for TEM, the DCD PCs appear to have higher intracellular electron density and appear darker than healthy PCs. In our experiments ten-month-old SCA2-58Q mice and age-matched nontransgenic mice were euthanized and transcardially perfused (according to [57]) with PBS followed by 2% paraformaldehyde/2% glutaraldehyde in 0.1M cacodylate buffer. The cerebellum was left in fixative overnight, subsequently cut into 1 mm3 coronal sections and post-fixed in 1% Osmium Tetroxide. The specimens were then stained en bloc with aqueous 1% uranyl acetate and lead citrate, dehydrated through a graded ethanol series, and embedded in EMbed 812 resin. Thinner sections (70–90 nm in thickness) were cut, placed on copper grids and stained with aqueous 2% uranyl acetate and lead citrate. Sections from each animal were examined on a FEI Tecnai G2 Spirit Biotwin transmission electron microscope, operated at 120 kV and digital images were captured with a SIS Morada 11 megapixel side mount CCD camera.

Consistent with our predictions, TEM of 10-month-old mice confirmed a continuous process of DCD in SCA2-58Q mice cerebellum (Fig. 2). PCs in age-matched nontransgenic mice appear normal with a regular alignment in the PC monolayer, spherical shape with clearly distinct nuclei and cytoplasm (Fig. 2a, c). PCs in SCA2-58Q mice show defects in spatial alignment resulting in PCs residing outside of the defined PC monolayer, evident shrinkage and darkened cytoplasm (Fig. 2b, d). For quantification of obtained results, PCs observed on TEM images were divided into three groups: normal (spherical, no darkening at all); moderately degenerated (slight shrinkage, moderately electron-dense cytosol not as dark as nucleus); or severely degenerated (markedly shrunken and electron-dense cytosol with similarly darkened nucleus). Quantitative analysis of TEM images showed that almost half of the PCs in SCA2-58Q mice are at the end-stage of degeneration with markedly shrunken, electron-dense cytosol with similarly darkened nucleus while the rest are moderately degenerated (Fig. 2g). This is in contrast to the age-matched wild type mice, where most cells are normal or only moderately affected (Fig. 2g). Degeneration does not seem to be limited to PCs in the cerebellum. Granule cells (GCs) in the granule cell layer, which form parallel fibers and serve as excitatory afferents to PCs, also appear to be degenerating in SCA2-58Q with evident cytoplasmic darkening and condensation when compared to those in nontransgenic mice (Fig. 2d, e). The degeneration of the granule cells are likely to be as a result of secondary toxicity as ATXN2-58Q transgene is expressed specifically in PC cells in the SCA2-58Q mouse model that we used [27]. From these results we concluded that PC cells in SCA2 transgenic mice undergo DCD form of cell death, consistent with the proposed excitotoxic hypothesis of SCA2 pathogenesis (Fig. 1). Interestingly, by using a calbindin staining and unbiased stereology approach we detected only 15% reduction in the number of PC cells in 12-month-old SCA2-58Q mice when compared to non-transgenic controls [17]. From this quantitative comparison it appears that many PCs undergoing DCD are still calbindin-positive. These cells are likely to be dysfunctional and contribute to ataxic symptoms. From these experiments we concluded that DCD analysis is a more sensitive way of scoring PC cell degeneration in SCA2 mice than calbindin-staining based stereological method.
Fig. 2.

PCs in aging SCA2 transgenic mice die by dark cell degeneration. Electron micrographs (×100 (a, b), ×610 (c, d), and ×1,400 (e, f) magnification) of the cerebellum from 10-month-old SCA2-58Q mice and age-matched nontransgenic mice. PCs in nontransgenic mice show regular alignment in Purkinje cell layer (arrows) (a), PCs show spherical shape (c), and healthy granule cells (GCs) (e). PCs in SCA2-58Q mice show defects in spatial alignment that results in PCs residing outside of the defined PC layer and evident shrinkage (arrows) (b), darkening of the cytoplasm and nuclei (d), and GCs in the granule cell layer appear to also be degenerating with evident cytoplasmic darkening and condensation (e). g Quantification of dark cell degeneration in the PC layer of 10-month-old SCA2 transgenic mice and nontransgenic controls (modified from [57]). Briefly, PCs were judged to be: normal (spherical, no darkening at all); moderately degenerated (slight shrinkage, moderately electron-dense cytosol not as dark as nucleus); or severely degenerated (markedly shrunken and electron-dense cytosol with similarly darkened nucleus). *P < 0.05, Mann–Whitney U test. Error bars represent standard deviation

Deranged Calcium Signaling in Other Polyglutamine SCAs

The Ca2+ hypothesis is not only relevant for SCA2 but can be expanded to other SCAs [7, 18, 21]. Deranged calcium signaling likely plays a role in the pathogenesis of SCA1. Similar to SCA2, SCA1 is caused by the translation of polyglutamine expansions in the gene encoding ataxin-1 from the normal 30 (ATXN1wt) to over 40 CAG repeats (ATXN1exp) (Table 1). ATXN1exp is widely expressed and selectively toxic in Purkinje cells [58]. Though its aggregation is not required to cause SCA1 pathology, ATXN1exp has to translocate to PC nuclei to cause cell death and ataxia [59]. In the nucleus, ATXN1exp alters transcription by destabilizing the RORα and SP-1 transcription factors [11, 60]. Microarray analyses of transgenic mouse models have shown that SCA1 mice may have altered calcium signaling. Early in SCA1 pathogenesis, SCA1 mice express significantly reduced levels of the calcium buffers calbindin and parvalbumin, ITPR1, type 1 inositol phosphate 5-phosphatase, ER calcium transporter SERCA, glutamate transporter EAAT4, EAAT4-stabilizer β-spectrin III, T-type volage gated calcium channels and transient receptor potential type 3 (TRPC3) calcium channels [9, 10, 11, 61]. Since ITPR1 and SERCA2 have contradictory roles on ER calcium storage, it is possible that ATXN1exp downregulates the expression of only one of the two. One mechanism may be that by blocking ER loading, SERCA2 downregulation causes higher cytoplasmic calcium levels and the PC counteracts this effect by downregulating ITPR1 expression, which decreases ER calcium release and reduce cytoplasmic calcium levels [62]. We suggest that decreased expression of glutamate transporters in SCA1 could result in excitotoxic glutamate signaling that is upstream of calcium signaling leading to cytosolic calcium overload. Similar hypothesis has been previously proposed to explain SCA1 phenotype [61]. Reduced expression of calcium buffers could also decrease the ability of PCs to handle high calcium levels in the cytoplasm. Furthermore, SCA1 mice crossed with calbindin-knockout mice presented with an accelerated SCA1 phenotype [10], which supports the role of calcium buffers in working to relieve SCA1 PCs from excitotoxic calcium levels and the role of deranged calcium homeostasis in the progression of SCA pathogenesis. We have also found that mutant ATXN1exp specifically interacts with ITPR1 (X.Chen and I. Bezprozvanny, unpublished observations). As we have seen in SCA2, this suggests that excessive calcium release from ER stores via ITPR1s may also contribute to pathogenesis of SCA1. Therefore it would be necessary to study SCA1 mouse models further for any other change in calcium signaling besides the already reported differences in gene expression of calcium signaling proteins [9, 10, 11].

Although we have outlined SCAs that display significant PC loss, aberrant calcium signaling may also play a role in the pathogenesis of other SCAs, such as for example SCA3 (Table 1). Although less than 25% of PCs are lost in SCA3 patients, we have found that deranged calcium signaling may also play a role in pathogenesis of SCA3. SCA3 is similar to SCA1 and SCA2 in that it is caused by a translation of polyglutamine expansions in the ataxin-3 (ATXN3) protein. But unlike SCA1 and SCA2, substantia nigra and pontine nuclei neurons are mainly affected with some PC death [2]. We have shown that polyglutamine expanded ATXN3exp specifically interacts with ITPR1, sensitizing it to activation by InsP3 [13]. Similar to SCA2, we found that feeding SCA3 transgenic mice with dantrolene results in alleviation of the age-dependent motor deficits, as well as the prevention of neuronal loss in both the substantia nigra and pontine nuclei [13].

SCA6 is caused by a polyglutamine expansion in the C terminus of a P/Q-type calcium channel, CaV2.1 (Table 1). It has been reported that this mutation enhances P/Q-type Ca2+ channels activity [63]. However, recent analysis of SCA6 knock-in mouse model indicated that pathology may be related to aggregation of mutant CaV2.1 subunits and reduction in the density of dendritic P/Q-type Ca2+ currents [16]. Animals expressing polyQ expanded CaV2.1 subunit exhibit age-dependent motor deficits and lower expression of the CaV2.1 channels but no difference in calbindin staining of slices when compared to WT [16]. This further supports our hypothesis of ataxia preceding cell death as these animals are ataxic in the absence of significant cell death. Future functional studies will be needed to understand alterations in Ca2+ signaling in PC cells from SCA6 mice.

Deranged Calcium Signaling in Non-Polyglutamine SCAs

Abnormal neuronal calcium signaling is not restricted to polyQ-expansion ataxias [18]. In SCA5, mutant β-III spectrin (SPTBN2) is unable to stabilize the glutamate transporter, excitatory amino acid transporter (EAAT4) on the PC membrane (Table 1). This would allow extended glutamate activation in the parallel fiber-PC synapse and lead to excitotoxicity in SCA5 [64]. Recent genetic evidence indicated that SCA14 is caused by mutations in protein kinase Cγ (PKCγ). PKCγ is highly expressed in PCs [65] (Table 1). Eighteen of the 22 identified mutations in PKCγ decrease the ability of PKCγ to phosphorylate and inactivate TRPC3 channels, which allow sustained calcium influx into the cell and results in elevated cytosolic calcium levels [12]. These calcium elevations, if left uncontrolled, could become toxic and result in PC loss via excitotoxic cascades described above. The rest of the mutations suppress calcium influx likely by hyperphosphorylating and over-inactivating TRPC3 channels [12]. Suppression of calcium signaling has been shown to be a cause of apoptotic cell death [66]. Therefore, even though we have described excitotoxicity as one possible effect of SCA-associated gene mutations on calcium signaling and cell survival, suppression of calcium signaling could be equally as detrimental as increasing it.

Unlike most of the SCAs we have discussed above, SCA15 and SCA16 are a result not of excitotoxity but of suppressed cytosolic calcium signaling (Table 1). SCA15 is genetically linked to 5′ deletions, total deletions or missense mutation (P1059L) in the gene encoding ITPR1 and located in 3p26.1–p25.3 chromosomal region [14, 67]. Although initial studies of a SCA16 family suggested linkage to chromosome 8q22.1–24.1 [68], additional studies of the same family showed linkage to chromosome 3pter-p26.2 [69]. Initially point mutation in the 3′ untranslated region of the contactin 4 gene (CNTN4) located in the same region was implicated [69, 70], but more recent analysis demonstrated that the real cause of SCA16 is haploinsufficiency of ITPR1 expression due to heterozygous deletion of exons 1 to 48 of the ITPR1 gene [15]. Thus, SCA15 and SCA16 are the same disorder (SCA15/16), due to haploinsufficiency of ITPR1 (Table 1). Although, SCA15/16 is not polyQ disorder, aberrant calcium signaling is likely to play a role in pathogenesis given the high expression of ITPR1 in PCs [32], and their importance for stimulating BDNF production for PC dendritic morphology [71], and cerebellar plasticity [53]. There are at least two possible physiological roles of these alterations on ITPR1 function and calcium homeostasis in PC. A gain of function of ITPR1s could occur if the mutation or deletion causes constitutive activity or increased sensitivity to activation of the mutated protein. A loss of function could also occur if the mutation or deletion suppresses ITPR1 activation and signaling. Affected patients of SCA15/16 and mice with spontaneous mutations in ITPR1 express less ITPR1 protein [67]. As we await studies on the functional roles of the reported ITPR1 mutation and deletions in the pathogenesis of SCA15/16, we can only speculate that suppressed activity of ITPR1s in SCA15/16 may uncouple plasticity mechanisms in PCs. Indeed, ITPR1 knockout mice do not survive past postnatal day 20–23 and completely lack cerebellar LTD, although hippocampal LTD is unaffected and hippocampal LTP is partially intact [53, 71, 72, 73]. Thus, disruption of ITPR1 expression or function may result in cerebellar-specific phenotypes, as observed in SCA15/16 patients.

Deranged PC Calcium Signaling in Mouse Ataxic Mutants

The premise that abnormalities in PC calcium signaling cause PC death and cerebellar ataxia is supported by a study of moonwalker mice, which are mutant mice expressing a point mutation (T635A) in a conserved residue of the TRPC3 cation channel that is highly expressed in PCs and important for mGluR signaling [74, 75]. In this study, the moonwalker mice were found to exhibit a progressive loss of PCs and severe ataxia. The point mutation did not affect the expression pattern of the channel but did alter its mGluR-mediated gating by causing an abnormal occurrence of glutamate-induced channel opening and spiking at low mGluR-agonist concentrations. This effect was not seen in wildtype mice. Interestingly, the mutation is located at a site phosphorylated by PKCγ. An in vitro kinase assay showed that the mutated channel is unable to be phosphorylated [75], as reported in SCA14, which leads to hyperactivity of TRPC3 channels and sustained calcium influx into the cytoplasm [12]. This is likely the cause of pathogenesis in moonwalker mice.

Concluding Remarks and the Prospects for Therapeutic Development

We propose that abnormal Purkinje cells Ca2+ signaling plays an important role in pathogenesis of SCA2 and many other SCAs. We argue that disruptions in Purkinje cell calcium signaling lead to initial cerebellar dysfunction and ataxic symptoms and eventually proceed to Purkinje cell death. Many brain areas affected in SCAs have afferent and efferent connections to the cerebellum, hence cerebellar dysfunction could result in dysfunction in these brain areas as well. We speculate that the earlier clinical symptoms in these ataxias result from enhanced cerebellar LTD and uncoupling of synaptic plasticity mechanisms in PC cells from intracellular Ca2+ signaling. These responses may be compensatory and aimed at reducing excitotoxic load on PCs, but the same synaptic plasticity changes may lead to initial ataxic phenotypes and onset of the disease. Ion channel modulators may have therapeutic value at this early symptomatic stage of disease, as has been recently demonstrated in mouse model of episodic ataxia type 2 [76]. Eventually PCs succumb to excitotoxic cell death, leading to progression of the symptoms and eventual death. In the specific case of SCA2, deranged PC Ca2+ signaling results from pathological interactions between ATXN2exp and ITPR1 (Fig. 1). In other SCAs, different mechanims may be responsible for disruption of PC Ca2+ signaling (Table 1). The experimental test of the proposed hypothesis will require analysis of Ca2+ signaling in SCA mouse models.

Based on these ideas, we would like to propose that calcium blockers and stabilizers have potential utility for treatment of SCAs. Consistent with this idea, we previously demonstrated that long-term feeding with intracellular Ca2+ stabilizer dantrolene resulted in neuroprotective effect in mouse models of SCA2 and SCA3 [7, 13, 17]. Similarly, neuroprotective and LTD-inhibitory effects were demonstrated for a novel ITPR1 inhibitor T-558 [51]. If deranged calcium signaling can be identified as a common underlying mechanism in all or most of the SCAs irrespective of the genes they are genetically linked to, then therapy directed at stabilizing calcium levels could be used for patients who have been diagnosed with SCAs with identified associated genes and also help others who have been diagnosed with SCAs yet to be linked to a particular gene. Controlled clinical evaluation of Ca2+ blockers and stabilizers in SCA patients is necessary to test clinical importance of these ideas. Although dantrolene and T-558 may not be optimal candidates for clinical testing, we hope that more specific and potent “Ca2+ stabilizers” will be developed in the future and evaluated in clinical trials with ataxia patients.

Notes

Acknowledgements

A.K. is a Howard Hughes Medical Institute Med into Grad Scholar. I.B. is a holder of Carla Cocke Francis Professorship in Alzheimer's Research and supported by the McKnight Neuroscience of Brain Disorders Award. The work on SCA2 and SCA3 was supported by the National Organization for Rare Disorders, National Ataxia Foundation, Ataxia MJD Research Project, and the National Institutes of Health grants R01NS38082 and R01NS056224.

Conflicts of interest

Authors declare no conflicts of interest related to this article.

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of PhysiologyUT Southwestern Medical Center at DallasDallasUSA

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