Spinal Cerebellar Ataxia Research Articles

Carbonic anhydrase-8 regulates inflammatory pain by inhibiting the ITPR1-cytosolic free calcium pathway.

Calcium dysregulation is causally linked with various forms of neuropathology including seizure disorders, multiple sclerosis, Huntington’s disease, Alzheimer’s, spinal cerebellar ataxia (SCA) and chronic pain. Carbonic anhydrase-8 (Car8) is an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1), which regulates intracellular calcium release fundamental to critical cellular functions including neuronal excitability, neurite outgrowth, neurotransmitter release, mitochondrial energy production and cell fate. In this report we test the hypothesis that Car8 regulation of ITPR1 and cytoplasmic free calcium release is critical to nociception and pain behaviors. We show Car8 null mutant mice (MT) exhibit mechanical allodynia and thermal hyperalgesia. Dorsal root ganglia (DRG) from MT also demonstrate increased steady-state ITPR1 phosphorylation (pITPR1) and cytoplasmic free calcium release. Overexpression of Car8 wildtype protein in MT nociceptors complements Car8 deficiency, down regulates pITPR1 and abolishes thermal and mechanical hypersensitivity. We also show that Car8 nociceptor overexpression alleviates chronic inflammatory pain. Finally, inflammation results in downregulation of DRG Car8 that is associated with increased pITPR1 expression relative to ITPR1, suggesting a possible mechanism of acute hypersensitivity. Our findings indicate Car8 regulates the ITPR1-cytosolic free calcium pathway that is critical to nociception, inflammatory pain and possibly other neuropathological states. Car8 and ITPR1 represent new therapeutic targets for chronic pain.

Restoration of Central Programmed Movement Pattern by Temporal Electrical Stimulation-Assisted Training in Patients with Spinal Cerebellar Atrophy.

Disrupted triphasic electromyography (EMG) patterns of agonist and antagonist muscle pairs during fast goal-directed movements have been found in patients with hypermetria. Since peripheral electrical stimulation (ES) and motor training may modulate motor cortical excitability through plasticity mechanisms, we aimed to investigate whether temporal ES-assisted movement training could influence premovement cortical excitability and alleviate hypermetria in patients with spinal cerebellar ataxia (SCA). The EMG of the agonist extensor carpi radialis muscle and antagonist flexor carpi radialis muscle, premovement motor evoked potentials (MEPs) of the flexor carpi radialis muscle, and the constant and variable errors of movements were assessed before and after 4 weeks of ES-assisted fast goal-directed wrist extension training in the training group and of general health education in the control group. After training, the premovement MEPs of the antagonist muscle were facilitated at 50 ms before the onset of movement. In addition, the EMG onset latency of the antagonist muscle shifted earlier and the constant error decreased significantly. In summary, temporal ES-assisted training alleviated hypermetria by restoring antagonist premovement and temporal triphasic EMG patterns in SCA patients. This technique may be applied to treat hypermetria in cerebellar disorders. (This trial is registered with NCT01983670.)

Genetic Variants in Diseases of the Extrapyramidal System

Knowledge on the genetics of movement disorders has advanced significantly in recent years. It is now recognized that disorders of the basal ganglia have genetic basis and it is suggested that molecular genetic data will provide clues to the pathophysiology of normal and abnormal motor control. Progress in molecular genetic studies, leading to the detection of genetic mutations and loci, has contributed to the understanding of mechanisms of neurodegeneration and has helped clarify the pathogenesis of some neurodegenerative diseases. Molecular studies have also found application in the diagnosis of neurodegenerative diseases, increasing the range of genetic counseling and enabling a more accurate diagno-sis. It seems that understanding pathogenic processes and the significant role of genetics has led to many experiments that may in the future will result in more effective treatment of such diseases as Parkinson’s or Huntington’s. Currently used molecular diagnostics based on DNA analysis can identify 9 neurodegenerative diseases, including spinal cerebellar ataxia inherited in an autosomal dominant manner, dentate-rubro-pallido-luysian atrophy, Friedreich’s disease, ataxia with ocu-lomotorapraxia, Huntington's disease, dystonia type 1, Wilson’s disease, and some cases of Parkinson's disease.

Poster 525 Traumatic Tetraplegia in a Patient with Spinal Cerebellar Ataxia: A CNS Double Crush Phenomenon?: A Case Report

PM&RVolume 4, Issue 10S p. S370-S370 2012 AAPM&R Annual Assembly Abstract Poster 525 Traumatic Tetraplegia in a Patient with Spinal Cerebellar Ataxia: A CNS Double Crush Phenomenon?: A Case Report William Carter MD, MPH, William Carter MD, MPH Virginia Commonwealth University, Richmond, VA, United StatesSearch for more papers by this authorCamilo Castillo MD, Camilo Castillo MD Virginia Commonwealth University, Richmond, VA, United StatesSearch for more papers by this authorLance L. Goetz MD, Lance L. Goetz MD Virginia Commonwealth University, Richmond, VA, United StatesSearch for more papers by this authorWilliam McKinley MD, William McKinley MD Virginia Commonwealth University, Richmond, VA, United StatesSearch for more papers by this author William Carter MD, MPH, William Carter MD, MPH Virginia Commonwealth University, Richmond, VA, United StatesSearch for more papers by this authorCamilo Castillo MD, Camilo Castillo MD Virginia Commonwealth University, Richmond, VA, United StatesSearch for more papers by this authorLance L. Goetz MD, Lance L. Goetz MD Virginia Commonwealth University, Richmond, VA, United StatesSearch for more papers by this authorWilliam McKinley MD, William McKinley MD Virginia Commonwealth University, Richmond, VA, United StatesSearch for more papers by this author First published: 23 October 2012 https://doi.org/10.1016/j.pmrj.2012.09.1127Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume4, Issue10SOctober 2012Pages S370-S370 RelatedInformation

B03 Systematic interactome mapping: understanding the molecular principles of neurodegenerative diseases

Neurodegenerative diseases (NDs) such as Alzheimer9s disease (AD), Parkinson9s disease (PD), amyotrophic lateral sclerosis, Huntington9s disease (HD) or spinal cerebellar ataxias are progressive brain disorders characterised by the accumulation of insoluble protein aggregates in neurons and the extracellular space. To elucidate potential common pathological mechanisms in NDs, we created comprehensive interaction networks for various known neurodegenerative disease proteins (NDPs). Using an automated yeast two-hybrid system, we identified 16 353 protein-protein interactions for 449 bioinformatically selected target proteins, connecting 80 known NDPs. This information was used to generate networks for individual NDs such as AD or PD and to predict proteins that are connected to multiple NDs. We found, for example, that the diseases AD, PD, amyotrophic lateral sclerosis, HD, and spinal cerebellar ataxia 1 are connected via four proteins that link known NDPs such as huntingtin, TDP43, parkin, τ, ataxin-1 and SOD1. Analysis of gene expression data predicted that these four proteins are abnormally altered in brains of HD, PD, and AD patients, supporting their importance for disease pathogenesis. Moreover, utilising computational methods as well as cell-based assays we have identified 21 human proteins that influence polyQ-induced ataxin-1 misfolding and proteotoxicity in various disease model systems. By analysing the protein sequences of these modifiers, we discovered a recurrent presence of coiled-coil domains in ataxin-1 toxicity enhancers, while such domains were not present in suppressors. This suggests that coiled-coil domains contribute to the aggregation- and toxicity-promoting effects of modifiers in mammalian cells. Our studies contribute to a deeper understanding of protein misfolding and aggregation in different NDs and highlight potential therapeutic targets for further investigations.

Glial-Derived Prodegenerative Signaling in the Drosophila Neuromuscular System

We provide evidence for a prodegenerative, glial-derived signaling framework in the Drosophila neuromuscular system that includes caspase and mitochondria-dependent signaling. We demonstrate that Drosophila TNF-α (eiger) is expressed in a subset of peripheral glia, and the TNF-α receptor (TNFR), Wengen, is expressed in motoneurons. NMJ degeneration caused by disruption of the spectrin/ankyrin skeleton is suppressed by an eiger mutation or by eiger knockdown within a subset of peripheral glia. Loss of wengen in motoneurons causes a similar suppression providing evidence for glial-derived prodegenerative TNF-α signaling. Neither JNK nor NFκβ is required for prodegenerative signaling. However, we provide evidence for the involvement of both an initiator and effector caspase, Dronc and Dcp-1, and mitochondrial-dependent signaling. Mutations that deplete the axon and nerve terminal of mitochondria suppress degeneration as do mutations in Drosophila Bcl-2 (debcl), a mitochondria-associated protein, and Apaf-1 (dark), which links mitochondrial signaling with caspase activity in other systems.

Transgenic mice with SCA10 pentanucleotide repeats show motor phenotype and susceptibility to seizure: A toxic RNA gain‐of‐function model

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder manifested by ataxia and seizure. SCA10 is caused by a large expansion of an intronic ATTCT pentanucleotide repeat in the ATXN10 gene. We have recently postulated a toxic RNA-mediated gain of function in the pathogenesis of spinal cerebellar ataxia type 10 (SCA10). The spliced intron-9 RNA containing the expanded AUUCU repeat aggregates in SCA10 cells and sequesters hnRNP K. hnRNP K sequestration triggers the translocation of protein kinase Cδ (PKCδ) to mitochondria, leading to activation of caspase-3 and apoptosis. To confirm the toxic RNA-mediated gain of function, we generated a new transgenic mouse model in which the expanded pentanucleotide repeats are constructed in the 3'-untranslated region (3'UTR) to ensure transcription without translation of the repeat. We constructed an artificial transgene containing the SCA10 (ATTCT)(500) track within the 3'UTR of the LacZ gene driven by the rat prion promoter (PrP) and used this to generate a new transgenic mouse model for SCA10. We then examined these mice for neurological phenotypes and histopathological, molecular, and cellular changes. The transgenic mice showed irregular gait and increased seizure susceptibility at the age of 6 months, resembling the clinical phenotype of SCA10. The cerebral cortex, hippocampus, and pontine nuclei showed neuronal loss. The brains of these animals also showed molecular and cellular changes similar to those previously found in an SCA10 cell model. Expression of the expanded SCA10 AUUCU repeat within the 3'UTR of a gene results in neuronal loss with associated gait abnormalities and increased seizure susceptibility phenotypes, which resemble those seen in SCA10 patients. Moreover, these results bolster the idea that the SCA10 disease mechanism is mediated by a toxic RNA gain-of-function mutation of the expanded AUUCU repeat.

Mitochondrial Dysfunction and Oxidative Stress Contribute to the Pathogenesis of Spinocerebellar Ataxia Type 12 (SCA12)

Spinal cerebellar ataxia type 12 (SCA12) has been attributed to the elevated expression of ppp2r2b. To better elucidate the pathomechanism of the neuronal disorder and to search for a pharmacological treatment, Drosophila models of SCA12 were generated by overexpression of a human ppp2r2b and its Drosophila homolog tws. Ectopic expression of ppp2r2b or tws caused various pathological features, including neurodegeneration, apoptosis, and shortened life span. More detailed analysis revealed that elevated ppp2r2b and tws induced fission of mitochondria accompanied by increases in cytosolic reactive oxygen species (ROS), cytochrome c, and caspase 3 activity. Transmission electron microscopy revealed that fragmented mitochondria with disrupted cristae were engulfed by autophagosomes in photoreceptor neurons of flies overexpressing tws. Additionally, transgenic flies were more susceptible to oxidative injury induced by paraquat. By contrast, ectopic Drosophila Sod2 expression and antioxidant treatment reduced ROS and caspase 3 activity and extended the life span of the SCA12 fly model. In summary, our study demonstrates that oxidative stress induced by mitochondrial dysfunction plays a causal role in SCA12, and reduction of ROS is a potential therapeutic intervention for this neuropathy.

Cerebellar ataxias: news on genetics and the excitability of affected neurons

This month’s Journal Club will focus on three articles that deal with cerebellar ataxias. In the first article, a novel causative gene of spinal cerebellar ataxias was identified using exome sequencing. This study not only identifies a new gene, but also demonstrates that exome sequencing is a promising method to significantly reduce the time required for the identification of novel mutations. The second article deals with cortical excitability in episodic ataxia type 2, the most frequent cause of episodic ataxia. It shows an increased excitability in the motor cortex of patients with episodic ataxia. On the other hand, subjects with familial hemiplegic migraine who have mutations in the same calcium channel gene did not have changes compared to control subjects. In the third article, threshold tracking techniques were applied to study nerve excitability in vivo in patients with episodic ataxia type 1, which is caused by mutations of a fast potassium channel. This technique showed significant differences between affected patients and controls. Thus, this simple 15 min test may also be a useful clinical diagnostic tool to support the diagnosis of episodic ataxia type 1 with high sensitivity and specificity.

Mutant Huntingtin in Glial Cells Exacerbates Neurological Symptoms of Huntington Disease Mice

Huntington disease (HD) is caused by an expansion of the polyglutamine (polyQ) repeat (>37Q) in huntingtin (htt), and age of onset is inversely correlated with the length of the polyQ repeat. Mutant htt with expanded polyQ is ubiquitously expressed in various types of cells, including glia, but causes selective neurodegeneration. Our recent study demonstrated that expression of the N-terminal mutant htt with a large polyQ repeat (160Q) in astrocytes is sufficient to induce neurological symptoms in mice (Bradford, J., Shin, J. Y., Roberts, M., Wang, C. E., Li, X.-J., and Li, S. H. (2009) Proc. Natl. Acad. Sci. U.S.A. 106, 22480-22485). Because glia-neuron interactions are critical for maintaining the normal function and survival of neurons in the brain and because mutant htt is more abundant in neurons than in glial cells, it is important to investigate whether glial htt can still contribute to HD pathology when mutant htt is abundantly expressed in neuronal cells. We generated transgenic mice that express mutant htt with 98Q in astrocytes. Unlike our recently generated htt-160Q transgenic mice, htt-98Q mice do not show obvious neurological phenotypes, suggesting that the length of the polyQ repeat determines the severity of glial dysfunction. However, htt-98Q mice show increased susceptibility to glutamate-induced seizure. Mice expressing mutant htt in astrocytes were mated with N171-82Q mice that express mutant htt primarily in neuronal cells. Double transgenic mice expressing mutant htt in both neuronal and glial cells display more severe neurological symptoms and earlier death than N171-82Q mice. These findings indicate a role of glial mutant htt in exacerbating HD neuropathology and underscore the importance of improving glial function in treating HD.

Non–cell autonomous toxicity in neurodegenerative disorders: ALS and beyond

Selective degeneration and death of one or more classes of neurons is the defining feature of human neurodegenerative disease. Although traditionally viewed as diseases mainly affecting the most vulnerable neurons, in most instances of inherited disease the causative genes are widely—usually ubiquitously—expressed. Focusing on amyotrophic lateral sclerosis (ALS), especially disease caused by dominant mutations in Cu/Zn superoxide dismutase (SOD1), we review here the evidence that it is the convergence of damage developed within multiple cell types, including within neighboring nonneuronal supporting cells, which is crucial to neuronal dysfunction. Damage to a specific set of key partner cells as well as to vulnerable neurons may account for the selective susceptibility of neuronal subtypes in many human neurodegenerative diseases, including Huntington's disease (HD), Parkinson's disease (PD), prion disease, the spinal cerebellar ataxias (SCAs), and Alzheimer's disease (AD).

Polyglutamine Genes Interact to Modulate the Severity and Progression of Neurodegeneration in Drosophila

The expansion of polyglutamine tracts in a variety of proteins causes devastating, dominantly inherited neurodegenerative diseases, including six forms of spinal cerebellar ataxia (SCA). Although a polyglutamine expansion encoded in a single allele of each of the responsible genes is sufficient for the onset of each disease, clinical observations suggest that interactions between these genes may affect disease progression. In a screen for modifiers of neurodegeneration due to SCA3 in Drosophila, we isolated atx2, the fly ortholog of the human gene that causes a related ataxia, SCA2. We show that the normal activity of Ataxin-2 (Atx2) is critical for SCA3 degeneration and that Atx2 activity hastens the onset of nuclear inclusions associated with SCA3. These activities depend on a conserved protein interaction domain of Atx2, the PAM2 motif, which mediates binding of cytoplasmic poly(A)-binding protein (PABP). We show here that PABP also influences SCA3-associated neurodegeneration. These studies indicate that the toxicity of one polyglutamine disease protein can be dramatically modulated by the normal activity of another. We propose that functional links between these genes are critical to disease severity and progression, such that therapeutics for one disease may be applicable to others.

The cerebellum and migraine.

Clinical and pathophysiological evidences connect migraine and the cerebellum. Literature on documented cerebellar abnormalities in migraine, however, is relatively sparse. Cerebellar involvement may be observed in 4 types of migraines: in the widespread migraine with aura (MWA) and migraine without aura (MWoA) forms; in particular subtypes of migraine such as basilar-type migraine (BTM); and in the genetically driven autosomal dominant familial hemiplegic migraine (FHM) forms. Cerebellar dysfunction in migraineurs varies largely in severity, and may be subclinical. Purkinje cells express calcium channels that are related to the pathophysiology of both inherited forms of migraine and primary ataxias, mostly spinal cerebellar ataxia type 6 (SCA-6) and episodic ataxia type 2 (EA-2). Genetically driven ion channels dysfunction leads to hyperexcitability in the brain and cerebellum, possibly facilitating spreading depression waves in both locations. This review focuses on the cerebellar involvement in migraine, the relevant ataxias and their association with this primary headache, and discusses some of the pathophysiological processes putatively underlying these diseases.

Regulation of chloride ion conductance during skeletal muscle development and in disease. Focus on “Chloride channelopathy in myotonic dystrophy resulting from loss of posttranscriptional regulation for CLCN1”

productive investigations of disease mechanisms that also reveal new information about normal regulation elicit a particularly satisfying sense of a two-for-one deal. In the case of Lueck et al. (Ref. [13][1]; see page 1291 of this issue), a detailed study of the molecular basis for the myotonia (

A Purkinje cell whodunit

Compromised glutamate transport in Bergmann glia contributes to Purkinje cell death in a model of spinal cerebellar ataxia.

Non-coding? Nonsense!

The gene associated with spinal cerebellar ataxia 8 is transcribed in both directions to produce transcripts with CUG and CAG expansions.

RNAi: a potential therapy for the dominantly inherited nucleotide repeat diseases

Genetic diseases that are accompanied by central nervous system involvement are often fatal. Among these are the autosomal dominant neurogenetic diseases caused by nucleotide repeat expansion. For example, Huntington's disease (HD) and spinal cerebellar ataxia are caused by expansion of a tract of CAGs encoding glutamine. In HD and the other CAG-repeat expansion diseases, the expansion is in the coding region. Myotonic dystrophy is caused by repeat expansions of CUG or CCTG in noncoding regions, and the mutant RNA is disease causing. Treatments for these disorders are limited to symptomatic intervention. RNA interference (RNAi), which is a method for inhibiting target gene expression, provides a unique tool for therapy by attacking the fundamental problem directly. In this review, we describe briefly several representative disorders and their respective molecular targets, and methods to accomplish therapeutic RNAi. Finally, we summarize studies performed to date.

Childhood-onset ataxia: testing for large CAG-repeats in SCA2 and SCA7.

Infantile- and juvenile-onset spinal cerebellar ataxia (SCA) is associated with expansion of 130 to more than 200 CAG-repeats in the SCA2 and SCA7 genes. Routine clinical assays for SCA2 and SCA7, which use polymerase chain reaction (PCR) and denaturing PAGE (polyacrylamide gel electrophoresis), will not reliably detect such large expansions. An assay based on separation of PCR products on an agarose gel, blotting, and hybridization with a (CAG)6 oligonucleotide probe was used to test DNA from individuals more than 10 years of age who had a possible diagnosis of SCA. Among 25 cases, the PCR-blot assay confirmed the presence of SCA2 expansions between 230 and 500 repeats in four unrelated individuals, but did not detect any cases of extreme expansion in the SCA7 gene. The PCR-blot assay provides reliable detection of extreme expansion mutations. Routine incorporation of this assay in clinical laboratories may reveal that infantile-juvenile forms of SCA2 and SCA7 are more prevalent than previously recognized.

¿Tienen nuestros resúmenes (abstracts) lo que deben tener? Un análisis de la década 1991-2000

The autosomal dominant cerebellar ataxias (ADCA) type I are a group of neurological disorders that are clinically and genetically heterogeneous. Two genes implicated in the disease, SCA1 (spinal cerebellar ataxia 1) and SCA2, are already localized. We have mapped a third locus to chromosome 14q24.3-qter, by linkage analysis in a non-SCA1/non-SCA2 family and have confirmed its existence in a second such family. We suggest designating this new locus "SCA3". Combined analysis of the two families restricted the SCA3 locus to a 15-cM interval between markers D14S67 and D14S81. The gene for Machado-Joseph disease (MJD), a clinically different form of ADCA type I, has been recently assigned to chromosome 14q24.3-q32. Although the SCA3 locus is within the MJD region, linkage analyses cannot yet demonstrate whether they result from mutations of the same gene. Linkage to all three loci (SCA1, SCA2, and SCA3) was excluded in another family, which indicates the existence of a fourth ADCA type I locus.

The gene for Machado–Joseph disease maps to the same 3-cM interval as the spinal cerebellar ataxia 3 gene on chromosome 14q

Machado–Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder in families of Portuguese–Azorean ancestry. The gene responsible for MJD has been assigned to a 29-cM interval on chromosome 14q. A large Brazilian family with MJD was genotyped with six new microsatellite markers spanning 19 cM on chromosome 14q. Linkage analysis and haplotype reconstruction reduced the MJDcandidate region to a 3-cM interval between markers D14S280 and D14S81, permitting positional cloning. This interval also contains the spinal cerebellar ataxia 3( SCA3) gene, responsible for a genetic subtype of the type I autosomal dominant cerebellar ataxias, clinically related to MJD. This result supports the hypothesis that abnormalities in the same gene may be responsible for both disorders. The minor clinical differences between the two diseases may result from allelic heterogeneity.