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PubMed2004

Post-translational modifications in the survival motor neuron protein.

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by a progressive loss of the spinal motoneurons. The SMA-determining gene has been termed survival motor neuron (SMN) and is deleted or mutated in over 98% of patients. The encoded gene product is a protein expressed as different isoforms. In particular, we showed that the rat SMN cDNA produces two isoforms with M(r) of 32 and 35kDa, both localized in nuclear coiled bodies, but the 32kDa form is also cytoplasmic, whereas the 35kDa form is also microsomal. To determine the molecular relationship between these two isoforms and potential post-translational modifications, we performed transfection experiments with a double-tagged rat SMN. Immunoblot and immunostaining studies demonstrated that the 32kDa SMN isoform derives from the full length 35kDa, through a proteolytic cleavage at the C-terminal. Furthermore, the 35kDa SMN isoform is physiologically phosphorylated in vivo. This may modulate its interaction with molecular partners, either proteins or nucleic acids.

3T3 Cells↗
PubMed1998

Sequence of a 131-kb region of 5q13.1 containing the spinal muscular atrophy candidate genes SMN and NAIP.

The spinal muscular atrophies (SMA), which are characterized by motor neuron loss and progressive paralysis, are among the most common autosomal recessive disorders. The SMA region of chromosome 5q13.1 is distinguished by variable amplification of genomic sequence incorporating a number of genes and pseudogenes. Recently, two SMA candidate genes mapping to this area were identified: survival motor neuron (SMN) and neuronal apoptosis inhibitory protein (NAIP). The telomeric copy of SMN (SMNtel) is deleted in over 95% of cases of SMA, with NAIP deletions primarily seen in type I SMA. We present here 131 kb of genomic sequence from 5q13.1 incorporating both NAIP and SMNtel in addition to revisions of the original NAIP cDNA sequence. The Alu-rich NAIP-SMNtel interval contains the microsatellite polymorphisms that are deleted in as many as 80% of type I SMA chromosomes, focusing attention on this region in the pathogenesis of type I SMA.

Amino Acid Sequence↗
PubMed1989

Scoliosis in spinal muscular atrophy: review of 63 cases.

We reviewed the incidence and severity of scoliosis in 37 patients with the intermediate type and 26 with the mild type of spinal muscular atrophy. In the intermediate type, scoliosis has an early onset and rapid progression before puberty, and a spinal fusion will be needed in virtually all cases. This rapid progression occurred despite routine use of a spinal brace. Hip dislocation was frequently present but, in most cases, was secondary to the pelvic tilt and did not contribute to the scoliosis. In the mild type, the scoliosis was more variable. In the 30% of patients who had scoliosis, progression was rapid during puberty but only in those who had lost ambulation. Of the four children with the intermediate type and the seven with the mild type who walked in light-weight orthoses, progression of scoliosis was slow, except in those who had lost ambulation. The ultimate effect of walking in orthoses is difficult to assess because of small numbers, but it seems to slow or at least delay progressive scoliosis.

Adolescent↗
PubMed1994

[Monoclonal antibodies to dystrophin in biopsy diagnosis of Duchenne and Becker progressive muscular dystrophies].

Immunohistochemical method detecting dystrophin in muscle biopsies was introduced and applied in 121 cases with a large scale of neuromuscular diseases. A monoclonal antibody NCL-DYS 2 (Novocastra) was used for the detection of C-terminal domain of dystrophin. Normal, i.e. sarcolemmal, localization of dystrophin was found in controls, in inactivity atrophy, neurogenic lesions and congenital myopathies. A similar situation except regenerating fibres was found in myositis and progressive muscular dystrophies different from Duchenne (DMD) and Becker (BMD) types, DMD cases showed a complete or nearly complete loss of sarcolemmal reaction product, whereas a partial loss of dystrophin in membrane was found in BMD cases as well as in transmitter females. Fibres splitting during neurogenic and myogenic lesions had dystrophin in newly produced sarcolemmal parts. Sarcolemmal immunoreactivity starting as early as in the 10th-12th week of gestation was found in human fetuses.

Antibodies, Monoclonal↗
PubMed2003

Mutations in dynein link motor neuron degeneration to defects in retrograde transport.

Degenerative disorders of motor neurons include a range of progressive fatal diseases such as amyotrophic lateral sclerosis (ALS), spinal-bulbar muscular atrophy (SBMA), and spinal muscular atrophy (SMA). Although the causative genetic alterations are known for some cases, the molecular basis of many SMA and SBMA-like syndromes and most ALS cases is unknown. Here we show that missense point mutations in the cytoplasmic dynein heavy chain result in progressive motor neuron degeneration in heterozygous mice, and in homozygotes this is accompanied by the formation of Lewy-like inclusion bodies, thus resembling key features of human pathology. These mutations exclusively perturb neuron-specific functions of dynein.

Animals↗
PubMedDate not supplied

The otolaryngologic presentation of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a progressive dengenerative neuromuscular disease of insidious onset. It involves upper and lower motor neurons and causes both spastic and atrophic muscular symptoms. More than one fourth of patients have complaints relating to the head and neck (bulbar palsy); thus, the otolaryngologist may be the first physician to see them. Predominant symptoms are slurred speech, hoarseness, dysphagia, and dyspnea. Muscular weakness, atrophy, and fasciculation are noted on examination. The course is relentless, and only 20% of patients survive five years after diagnosis.

Adult↗
PubMedDate not supplied

Polyglutamine tract expansion of the androgen receptor in a motoneuronal model of spinal and bulbar muscular atrophy.

Spinobulbar muscular atrophy (SBMA) is a late-onset disorder characterized by progressive muscle loss, degeneration of motoneurons in the spinal cord and brainstem, and partial androgen insensitivity. SBMA is directly correlated with the expansion of CAG repeats encoding a polyglutamine tract (polyQ) of extended length. The identification of polyQ expansion in SBMA led to the discovery of an entire class of neurodegenerative disorders. In fact, at least eight different diseases, including Huntington's disease, share a common molecular mechanism involving an expansion of a polyQ tract within different proteins. The elongated polyQ tract causes a toxic gain of function in the mutant protein and is associated with the formation of intracellular aggregates, whose pathogenetic role has not been fully established yet. Our observations in a motoneuron cell line (NSC34), indicate that the expression of the androgen receptor (AR) carrying the elongated polyQ tract (AR-Q48) has a toxic effect in aggregate-independent manner. In fact, in basal condition, AR-Q48 shows a cytoplasmic diffuse distribution, yet it reduces the viability of transfected NSC34. In contrast, testosterone treatment, while inducing aggregation of the mutant AR, also increases cell viability. Aggregates in NSC34 are localized mainly in the perinuclear region and occasionally in the neuropil, whereas no nuclear aggregate has ever been found. Further observations of the minor subset of cells showing neuropil aggregates, reveal an alteration of the neurite morphology, suggesting a different role of the two types of cytoplasmic aggregates.

Humans↗
PubMed1988

Descriptive epidemiology of some rare neurological diseases in Benghazi, Libya.

During a 4-year study period, January 1983 to December 1986, 24 patients (18 index cases) with spinal muscular atrophy (hereditary motor neuropathy, HMN), 9 with myasthenia gravis (MG), 6 with progressive supranuclear palsy (PSP), and 5 with subacute sclerosing panencephalitis (SSPE) were diagnosed in Benghazi. The HMN group comprised 6 acute infantile, 12 chronic childhood, and 3 each with adult-onset proximal, and distal forms of the disease. The crude average annual incidence of acute infantile HMN was 0.3/100,000 total population and 1/12,500 births in Benghazi. The crude prevalence rates of chronic childhood, adult-onset proximal, and distal types of HMN were 2.3, 0.6 and 0.6/100,000, respectively. The larger family size and the high rate of consanguineous marriages contribute to the high frequency of HMN in the study area. Distal HMN constituted 12.5% of the total cases. The adjusted average incidence of MG was 4.4/million/year, 2.1 for males and 6.8 for females. The female:male incidence ratio was 3.2:1. The crude average annual incidence rates/million inhabitants for PSP asnd SSPE were 3 and 2.4, respectively. The frequency of occurrence of SSPE among the subtropical Arab community under investigation is comparable with other surveys from the Middle East and Mediterranean region.

Adolescent↗
PubMed1986

Activation of mitochondrial ATPase as evidence of loosely coupled oxidative phosphorylation in various skeletal muscle disorders. A histochemical fine-structural study.

Combined histochemical and biochemical studies have shown, that the histochemical activity of mitochondrial Mg2+-activated ATPase closely correlates with the coupling state of oxidative phosphorylation (Meijer and Vloedman 1980). Using this histochemical method 646 unselected skeletal muscle biopsies have been investigated. Activation of the enzyme, i.e. loosely coupled mitochondria were present either focally or diffusely expressed in 28% of the biopsies irrespective of the underlying disorder. Most often it was found in mitochondrial myopathies and in progressive muscular dystrophy type Duchenne; in a lesser degree it was also present in neurogenic atrophy and in various other disorders. Ninety two percent of all cases with loose coupling showed mitochondrial proliferations. On the other hand in 20% of all cases with mitochondrial proliferations including 19 cases of diffuse mitochondrial myopathy and 3 of progressive external ophthalmoplegia no activation of the enzyme was found. The results show that loose coupling is closely but not absolutely associated with mitochondrial proliferation, it is present in mitochondrial myopathies but also in various other muscular disorders with different pathogenesis.

Adenosine Triphosphatases↗
PubMed2006

Pathogenesis, animal models and therapeutics in spinal and bulbar muscular atrophy (SBMA).

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neurodegenerative disease characterized by slowly progressive muscle weakness and atrophy of bulbar, facial, and limb muscles. The cause of SBMA is expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, in the first exon of the androgen receptor (AR) gene. SBMA chiefly occurs in adult males, whereas neurological symptoms are rarely detected in females having mutant AR gene. The cardinal histopathological finding of SBMA is loss of lower motor neurons in the anterior horn of spinal cord as well as in brainstem motor nuclei. Animal models carrying human mutant AR gene recapitulate polyglutamine-mediated motor neuron degeneration, providing clues to the pathogenesis of SBMA. There is increasing evidence that testosterone, the ligand of AR, plays a pivotal role in the pathogenesis of neurodegeneration in SBMA. The striking success of androgen deprivation therapy in SBMA mouse models has been translated into clinical trials. In addition, elucidation of pathophysiology using animal models leads to emergence of candidate drugs to treat this devastating disease: HSP inducer, Hsp90 inhibitor, and histone deacetylase inhibitor. Utilizing biomarkers such as scrotal skin biopsy would improve efficacy of clinical trials to verify the results from animal studies. Advances in basic and clinical researches on SBMA are now paving the way for clinical application of potential therapeutics.

Animals↗
PubMed1983

[Tumor-like transformation of the median nerve in neural muscular atrophy].

This paper reports a case of local enlargement of the median nerve in the upper arm due to the very rare condition of hypertrophic neuropathy. A characteristic feature of this affection of peripheral nerves, the cause of which is unknown, is the onion-skin-like hypertrophy of the Schwann cells and chronic neurogenic muscular atrophy. The examination of the nerve distension is described. The appropriate treatment is not known; however, the prognosis is favourable in cases showing very slow progression.

Adult↗
PubMed2006

Progressive alterations in the hypothalamic-pituitary-adrenal axis in the R6/2 transgenic mouse model of Huntington's disease.

Huntington's disease (HD) is characterized by a triad of motor, psychiatric and cognitive symptoms. Although many of these symptoms are likely to be related to central nervous system pathology, others may be due to changes in peripheral tissues. The R6/2 mouse, a transgenic model of HD expressing exon 1 of the human HD gene, develops progressive alterations in the hypothalamic-pituitary-adrenal axis, reminiscent of a Cushing-like syndrome. We observed muscular atrophy, reduced bone mineral density, abdominal fat accumulation and insulin resistance in the mice. All these changes could be consequences of increased glucocorticoid levels. Indeed, hypertrophy of the adrenal cortex and a progressive increase in serum and urine corticosterone levels were found in R6/2 mice. In addition, the intermediate pituitary lobe was markedly enlarged and circulating adreno-corticotrophic hormone (ACTH) increased. Under normal conditions dopamine represses the ACTH expression. In the R6/2 mice, however, the expression of pituitary dopamine D2 receptors was reduced by half, possibly explaining the increase in ACTH. Urinary samples from 82 HD patients and 68 control subjects were analysed for cortisol: in accord with the observations in the R6/2 mice, urinary cortisol increased in parallel with disease progression. This progressive increase in cortisol may contribute to the clinical symptoms, such as muscular wasting, mood changes and some of the cognitive deficits that occur in HD.

Adrenocorticotropic Hormone↗
PubMed1985

A Fukuyama type of congenital muscular dystrophy associated with atypical gyrate atrophy of the choroid and retina. A case report.

A three-year-ten-month old boy with the Fukuyama type of congenital muscular dystrophy (FCMD), early onset of muscular hypotonia, severe mental retardation, a slow progressive course and a characteristic fundus appearance similar to that of gyrate atrophy is described. Hyperornithinaemia and iminoglycinuria were not noted. To our knowledge, this is the first reported case of FCMD associated with atypical gyrate atrophy of the choroid and retina.

Amino Acids↗
PubMed1996

[Metabolic changes in denervated skeletal muscles].

Section of the motor nerve of skeletal muscles produces severe atrophy and causes dramatic changes in biochemical properties of the muscles. Progressive decrease of oxidative and glycolytic activity, increased protein and purine degradation are prominent features of muscular atrophy. Denervation leads also to rapidly developing insulin resistance in skeletal muscles.

Animals↗
PubMed2006

Genetics of familial and sporadic amyotrophic lateral sclerosis.

Diseases affecting motor neurons, such as amyotrophic lateral sclerosis (Lou Gerhig's disease), hereditary spastic paraplegia and spinal bulbar muscular atrophy (Kennedy's disease) are a heterogeneous group of chronic progressive diseases and are among the most puzzling yet untreatable illnesses. Over the last decade, identification of mutations in genes predisposing to these disorders has provided the means to better understand their pathogenesis. The discovery 13 years ago of SOD1 mutations linked to ALS, which account for less than 2% of total cases, had a major impact in the field. However, despite intensive research effort, the pathways leading to the specific motor neurons degeneration in the presence of SOD1 mutations have not been fully identified. This review provides an overview of the genetics of both familial and sporadic forms of ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2006

Cellular therapies in motor neuron diseases.

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are prototypical motor neuron diseases that result in progressive weakness as a result of motor neuron dysfunction and death. Though much work has been done in both diseases to identify the cellular mechanisms of motor neuron dysfunction, once motor neurons have died, one of potential therapies to restore function would be through the use of cellular transplantation. In this review, we discuss potential strategies whereby cellular therapies, including the use of stem cells, neural progenitors and cells engineered to secrete trophic factors, may be used in motor neuron diseases. We review pre-clinical data in rodents with each of these approaches and discuss advances and regulatory issues regarding the use of cellular therapies in human motor neuron diseases.

Amyotrophic Lateral Sclerosis↗
PubMed2005

Correction of SMN2 Pre-mRNA splicing by antisense U7 small nuclear RNAs.

Mutations in one of the duplicated survival of motor neuron (SMN) genes lead to the progressive loss of motor neurons and subsequent development of spinal muscular atrophy (SMA), a common, and usually fatal, hereditary disease. Homozygous absence of the telomeric copy (SMN1) correlates with development of SMA because differential splicing of the centromeric copy (SMN2) leads to exon 7 skipping and predominantly produces a biologically inactive protein isoform. To increase exon 7 inclusion of SMN2, we have designed a series of vectors that express modified U7 snRNAs containing antisense sequences complementary to the 3' splice site of SMN exon 8. Over 20 anti-SMN U7 snRNAs were tested for their ability to promote exon 7 inclusion in the SMN2 gene. Transient expression of anti-SMN U7 snRNAs in HeLa cells modulated SMN2 splicing to approximately 70% exon 7 inclusion in a sequence-specific and dose-dependent manner. Significantly, the administration of anti-SMN U7 snRNPs results in an increase in the concentration of SMN protein. These results suggest that modulation of SMN2 pre-mRNA splicing by modified U7 snRNAs provides a promising form of gene therapy for the treatment of SMA.

Blotting, Western↗