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PubMed1998

Cleavage, aggregation and toxicity of the expanded androgen receptor in spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by the expansion of a polyglutamine repeat within the androgen receptor (AR). We have studied the mutant AR in an in vitro system, and find both aggregation and proteolytic processing of the AR protein to occur in a polyglutamine repeat length-dependent manner. In addition, we find the aberrant metabolism of expanded repeat AR to be coupled to cellular toxicity, indicating a likely molecular basis for the toxic gain of AR function that produces neuronal degeneration in SBMA.

Animals↗

PubMed1999

Deletion analysis in Turkish patients with spinal muscular atrophy.

Childhood proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder which presents as a severe, intermediate or mild condition. Here we present the molecular analysis of SMA candidate genes, the survival motor neuron gene (SMN), the neuronal apoptosis inhibitory protein gene (NAIP) and the p44 gene. Deletion frequency rate of these candidate genes is 93% in 106 Turkish SMA patients. Various deletion haplotypes by using genotypes of SMN, NAIP and p44 genes are constructed. Haplotype A, which is the deletion of all three involved genes, was found only in the most severe group with an early onset of usually less than 2 months of age.

Cyclic AMP Response Element-Binding Protein↗

PubMed1999

Migrating atelectasis in Werdnig-Hoffmann disease: pulmonary manifestations in two cases of spinal muscular atrophy type 1.

Spinal muscular atrophy (SMA) or Werdnig-Hoffmann disease is the second most common neuromuscular disease, with 25% of cases presenting in infancy. Deletions in the survival motor neuron gene are believed responsible for autosomal-recessive SMA. SMA affects about 1 in 10,000 births. Symptomatic newborns have severe hypotonia, may have respiratory distress, may be unable to feed, and rapidly progress to death early in infancy. This paper describes another early pulmonary manifestation of SMA, i.e., migrating or rotating atelectasis, in 2 patients with infantile SMA. Migrating or rotating atelectasis may suggest the diagnosis of SMA.

Humans↗

PubMed1984

Autosomal dominant inheritance of hereditary canine spinal muscular atrophy.

Hereditary canine spinal muscular atrophy ( HCSMA ) is a motor neuron disease in Brittany spaniels. Three phenotypes are recognized (accelerated, intermediate, and chronic) and are distinguished on the basis of rate of progression and age at onset. Breeding studies within a kindred of more than 125 dogs (Brittany spaniel and beagle-Brittany outcrosses ) have established an autosomal dominant inheritance for HCSMA . Pups homozygous for the trait have accelerated disease whereas heterozygous dogs have intermediate or chronic disease. The reason for the two phenotypes in heterozygotes is under study. HCSMA provides a unique opportunity to study the genetic and pathophysiological mechanisms of a motor neuron disease, and findings may have broad relevance to investigations of autosomal dominant degenerative disorders of the central nervous system.

Animals↗

PubMed2004

Analysis of the survival motor neuron and neuronal apoptosis inhibitory protein genes in Malay patients with Spinal Muscular Atrophy.

In Malaysia, Spinal Muscular Atrophy (SMA) is diagnosed based on clinical observation with or without muscle biopsy. Molecular analyses of the SMA-related genes have not been available so far. In this preliminary study, we searched for homozygous deletion of Survival Motor Neuron (SMN1) and Neuronal Apoptosis Inhibitory Protein (NAIP) genes in Malay patients with SMA and found homozygous deletion of SMN1 exon 7 and 8 in all the patients while homozygous deletion of NAIP exon 5 was detected in only our type 1 patients but not in the type 3 patient. To the best of our knowledge, these are the first SMA cases diagnosed at the molecular level in Malaysia.

Cyclic AMP Response Element-Binding Protein↗

PubMed1999

[In vitro aggregation and cellular toxicity of mutant androgen receptor protein in spinal and bulbar muscular atrophy].

Spinal and bulbar muscular atrophy (SBMA) is an X-linked motor caused by expansion of a polyglutamine repeat within the androgen receptor(AR). We have studied the mutant AR in an in vitro system, and find aggregation of the AR protein to occur in a polyglutamine repeat length-dependent manner and the cellular toxicity to be coupled to aggregation. In addition we find intranuclear inclusions in nonneural tissues as well as affected neural tissues. These results indicate that the polyglutamine repeat length-dependent aggregation may be a likely molecular basis for the toxic gain of AR function that produces neuronal degeneration in SBMA. However, there is a recent report which suggests that inclusions did not correlate with cell death. Thus the mechanism of toxic gain of function remains to be elucidated.

Cell Death↗

PubMed1999

[Transcriptional regulation and subcellular localization of mutant androgen receptor in spinal and bulbar muscular atrophy].

Spinal and bulbar muscular atrophy (SBMA) is an adult form of motor neuronopathy with X-linked recessive hereditary trait, whose genetic mutation is an expansion of CAG repeats in the androgen receptor(AR) gene. The effect of the expansion of the polyglutamine stretch in AR protein has been investigated in several lines of experiments. The binding ability of androgen to AR is similar to control, but AR binding affinity to androgen responsive element(ARE) is increased in mutant AR, and AR-induced transcriptional activation decreases with increasing glutamine repeats. The subcellular localization of mutant AR may be variable among the tissues, but intranuclear inclusion of mutant AR occurs ubiquitously in neural and non-neural tissues. Therefore the expansion in the polyglutamine stretch may induce some pathological aberrations in transcriptional regulation and translocation of AR in SBMA.

Adult↗

PubMed1995

Deletions in the survival motor neuron gene on 5q13 in autosomal recessive spinal muscular atrophy.

Autosomal recessive spinal muscular atrophy is a motor neuron disease which affects about 1 in 10,000 births. Recent evidence shows that the candidate region contains multiple copies of genes and pseudogenes and is characterised by genome instability. We have analysed the frequency of deletions in a recently characterised candidate survival motor neuron (SMN) gene. Our data confirm previous analyses and show that this gene is disrupted by deletion in SMA patients. The same deletion frequency is observed in the milder variants of the disease as in patients with the severe form. In addition, we observed one case of a new mutation in a family previously thought not to be segregating for a chromosome 5 linked form of SMA. This assay is a very good diagnostic for SMA although no direct correlation between phenotype and genotype is apparent and carrier status cannot be determined. The implications for the identification of the gene or genes causing the disease are discussed.

Chromosomes, Human, Pair 5↗

PubMed2006

Abolishing Bax-dependent apoptosis shows beneficial effects on spinal muscular atrophy model mice.

Spinal muscular atrophy (SMA) is the most common genetic motoneuron degenerative disorder, but the mechanism(s) of motoneuron degeneration is unclear. We previously generated SMA model mice, which genotypically and phenotypically mimicked human SMA patients, by a combination of knockout and transgenic techniques. Here, we used these SMA model mice to decipher the apoptotic mechanism(s) involved in SMA motoneuron degeneration. We found a significant increase in proapoptotic Bax expression in the spinal cords of SMA mice in comparison with their wild-type littermates. After crossing SMA mice with Bax knockout mice, we produced in vivo evidence indicating that Bax protein plays an important role in the degeneration of SMA spinal motoneurons. Progeny Bax-deficient SMA mice showed milder disease severity, longer life spans, and significant increases in spinal motoneuron densities compared to SMA littermates with wild-type Bax genes. Our results strongly suggest that suppression of Bax-involved apoptosis has the potential for amelioration of SMA.

Animals↗

PubMed2003

Valproic acid increases SMN levels in spinal muscular atrophy patient cells.

Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by mutation of the telomeric copy of the survival motor neuron gene (SMN1). Although a centromeric copy of the survival motor neuron gene (SMN2) is retained in all patients with SMA, it differs from SMN1 at a critical nucleotide such that the majority of SMN2 transcripts lack exon 7 and encode an unstable, truncated protein. Here, we show that valproic acid increases levels of exon 7-containing SMN transcript and SMN protein in type I SMA patient-derived fibroblast cell lines. Valproic acid may increase SMN levels both by activating the SMN promoter and by preventing exon 7 skipping in SMN transcripts. Valproic acid and related compounds warrant further investigation as potential treatment for SMA.

Anticonvulsants↗

PubMed1992

Clinical variability of autosomal dominant spinal muscular atrophy.

Autosomal dominant spinal muscular atrophy (SMA) is generally classified into a juvenile and an adult onset form. Clinical data of 20 affected members out of 6 families with autosomal dominant proximal SMA are reported. Three families could largely be classified as the adult onset form (onset after 20 years of life). They showed a benign course, most of them remaining ambulatory 10-40 years after clinical onset. Intrafamilial variability of onset was small, the progression of weakness within one family appeared to be very similar. Three patients of the other 3 families suffered from the juvenile onset form (first symptoms before the age of 12 years) with walking difficulties throughout life, whereas other family members would have been classified as adult onset SMA. The latter had an onset between age 17 and 28 years, and were only moderately handicapped when last examined (aged 38-60 years). The great intrafamilial variability in at least some of the families with autosomal dominant SMA is not compatible with the distinction of two clinically defined genetic entities. This observation is important with respect to a reliable prediction in clinical practice and genetic counselling.

Adolescent↗

PubMed2002

Ligand promotes intranuclear inclusions in a novel cell model of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is one of a group of progressive neurodegenerative diseases resulting from a polyglutamine repeat expansion. In SBMA the polymorphic trinucleotide CAG repeat in exon 1 of the androgen receptor (AR) gene is increased, resulting in expansion of a polyglutamine tract. Patient autopsy material reveals neuronal intranuclear inclusions (NII) in affected regions that contain only amino-terminal epitopes of the AR. Cell models have previously been unable to produce intranuclear inclusions containing only a portion of the AR. We report here the creation of an inducible cell model of SBMA that reproduces this important characteristic of disease pathology. PC12 cells expressing highly expanded AR form ubiquitinated intranuclear inclusions containing amino-terminal epitopes of the AR as well as heat shock proteins. Inclusions appear as distinct granular electron-dense structures in the nucleus by immunoelectron microscopy. Dihydrotestosterone treatment of mutant AR-expressing cells results in increased inclusion load. This model mimics the formation of ubiquitinated intranuclear inclusions containing the amino-terminal portion of AR observed in patient tissue and reveals a role for ligand in the pathogenesis of SBMA.

Animals↗

PubMed2004

Reduced expression of nicotinic AChRs in myotubes from spinal muscular atrophy I patients.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by degeneration of motoneurons and skeletal muscle atrophy. In its most severe form, it leads to death before the age of 2 years. While primary degeneration of motor neurons is well established in this disease, and this results in neurogenic atrophy of skeletal muscle, we have previously reported evidence for a primary muscle defect. In this study, we used primary cultures of embryonic human skeletal muscle cells from patients with SMA and from controls to examine the effects of muscle fiber differentiation in the absence of a nerve component. Cultured SMA skeletal muscle cells are unable to fuse correctly to form multinuclear myotubes, the precursors of the myofibers. We also show that agrin-induced aggregates of nicotinic acetylcholine receptors, one of the earliest steps of neuromuscular junction formation, cannot be visualized by confocal microscopy on cells from SMA patients. In binding experiments, we demonstrate that this lack of clustering is due to defective expression of the nicotinic acetylcholine receptors in the myotubes of SMA patients whereas the affinity of alpha-bungarotoxin for its receptor remains unchanged regardless of muscle cell type (SMA or control). These observations suggest that muscle cells from SMA patients have intrinsic abnormalities that may affect proper formation of the neuromuscular junction.

Agrin↗

PubMed1999

[Utility and intricacy of molecular diagnosis of spinal muscular atrophy].

To diagnose spinal muscular atrophy (SMA), we examined the deletion of exons 7 and 8 of the survival motor neuron (SMN) gene and exon 5 of the neuronal apoptosis inhibitory protein (NAIP) gene in 7 patients from 6 unrelated families, using the polymerase chain reaction method. Two patients with type I and two with type II SMA had the deletion in SMN, whereas 2 of the 3 patients with type III had no deletion in these genes. Thus, the method was not as useful in type III as in type I and II for making a diagnosis of SMA. Together with the data previously reported by others, our data indicated the possibility that the deletion frequency in type III SMA is lower in Japanese patients (< 40%) than in non-Japanese patients (> 80%). Two siblings had SMA of different severity; the older brother having type III and the younger brother type II. Both had the same deletion in the SMN gene. The different phenotypes in these siblings with the same genotype indicated that caution is required when utilizing molecular data for genetic counseling or prenatal diagnosis of SMA.

Child↗

PubMed2006

Abolishing Trp53-dependent apoptosis does not benefit spinal muscular atrophy model mice.

Spinal muscular atrophy (SMA) is the most common genetic motoneuron degenerative disorder, but the mechanism(s) of motoneuron death is unclear. Previously, a direct interaction between tumor-suppressive TP53 protein and the SMA determinant gene product, survival motor neuron protein, was identified and therefore it has been suggested that a mechanism of TP53-dependent apoptosis plays an important role in motoneuron degeneration in SMA. We used our SMA model mice, generated by a combination of knockout and transgenic techniques, to decipher the role of TP53 protein in the motoneuron degeneration in SMA. We detected a significant increase of Trp53 expression in the spinal cord of SMA-like mice compared to their normal littermates. After crossing SMA-like mice with Trp53 knockout mice, the progeny Trp53-deficient SMA-like mice did not show milder disease severity or longer lifespan compared to SMA littermates with wild-type Trp53 genes. Our studies provide in vivo evidence indicating that Trp53-dependent apoptosis does not play a crucial role in motoneuron degeneration in SMA-like mice. European Journal of Human Genetics (2006) 14, 372-375. doi:10.1038/sj.ejhg.5201556; published online 4 January 2006.

Animals↗

PubMed2002

Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is one of a growing number of neurodegenerative diseases caused by a polyglutamine-encoding CAG trinucleotide repeat expansion, and is caused by an expansion within exon 1 of the androgen receptor (AR) gene. The family of polyglutamine diseases is characterized by the presence of ubiquitinated, intranuclear inclusions associated with molecular chaperones and 26S proteasome components, although the role of these inclusions in the pathogenesis of polyglutamine diseases remains unclear. The over-expression of molecular chaperones of the Hsp70 and Hsp40 families has been shown to modulate inclusion frequency and cellular toxicity. We developed a cell culture system which enables the quantitative analysis of the effects of molecular chaperones on the biochemical properties of an expanded repeat AR. Using this approach, we demonstrate that Hsp70 and its co-chaperone Hsp40 not only increase expanded repeat AR solubility, but function to enhance the degradation of expanded repeat AR through the proteasome. Furthermore, our studies indicate that these molecular chaperones significantly decrease the half-life of an expanded repeat AR. Molecular chaperone enhancement of protein degradation points to the modulation of molecular chaperones as a potential therapeutic target for polyglutamine diseases.

Acetylcysteine↗

PubMed2001

Spinal muscular atrophy: present state.

Spinal muscular atrophy (SMA) is a hereditary neurodegenerative disease caused by homozygous deletions or mutations in the SMN1 gene on Chr.5q13. SMA spans from severe Werdnig-Hoffmann disease (SMA 1) to relatively benign Kugelberg-Welander disease (SMA 3). Onset before birth possibly aggravates the clinical course, because immature motoneurons do not show compensatory sprouting and collateral reinnervation, and motor units in SMA 1, in contrast to those in SMA 3, are not enlarged. Genetic evidence indicates that SMN2, a gene 99% identical to SMN1, can attenuate SMA severity: in patients, more SMN2 copies and higher SMN protein levels are correlated with milder SMA. There is evidence that SMN plays a role in motoneuron RNA metabolism, but it has also been linked to apoptosis. Several mouse models with motoneuron disease have been successfully treated with neurotrophic factors. None of these models is, however, homologous to SMA. Recently, genetic mouse models of SMA have been created by introducing human SMN2 transgenes into Smn knockout mice or by targeting the Smn gene knockout to neurons. These mice not only provide important insights into the pathogenesis of SMA but are also crucial for testing new therapeutic strategies. These include SMN gene transfer, molecules capable to up-regulate SMN expression and trophic or antiapoptotic factors.

Adenosine Triphosphatases↗

PubMed1998

Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is an X-linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. To study AR protein expression in normal and SBMA individuals, we used several antibodies that recognize AR protein, and analyzed neural and nonneural tissues by immunohistochemistry and western blotting. Both the normal and the mutant AR proteins were widely distributed, predominantly, but not exclusively, in the cytoplasm of neurons regardless of the pathological involvement, and predominantly in the nuclei of the nonneural tissues in both normal and SBMA individuals, with different expression levels of AR protein among different tissues. In the motor neurons of SBMA patients, there were AR-immunoreactive ubiquitinated nuclear inclusions that were detected by antibodies that recognize a small portion of the N terminus of the AR protein. Absence of other immunoreactive AR epitopes within the inclusion may be due to altered AR configuration, or masking of AR epitopes by other proteins, or proteolytic cleavage of the AR. Our data show that, in addition to the normal cellular distribution of the AR protein, mutant AR-bearing nuclear inclusions are present in SBMA.

Aged↗