ABSTRACT
This article was retracted by author's request.
Subject(s)
Axons/pathology , Brain Diseases/pathology , Brain/pathology , Calcinosis/pathology , Corpus Callosum/pathology , Leukoencephalopathies/pathology , Neuroglia/pathology , Spheroids, Cellular/pathology , Adult , Atrophy , Brain/diagnostic imaging , Brain Diseases/diagnostic imaging , Calcinosis/diagnostic imaging , Corpus Callosum/diagnostic imaging , Diagnosis, Differential , Humans , Leukoencephalopathies/diagnostic imaging , Magnetic Resonance Imaging , Male , Pigmentation , Time Factors , Tomography, X-Ray ComputedABSTRACT
OBJECTIVE: To characterize the phenotype of spinocerebellar ataxia type 36 (SCA36), a novel dominant disorder (nicknamed "Asidan") caused by a hexanucleotide GGCCTG repeat expansion in intron 1 of the NOP56 gene. METHODS: We investigated the clinical, genetic, and neuropathologic characteristics of 18 patients with SCA36. We performed histologic evaluation of a muscle biopsy specimen from 1 patient with SCA36, and neuropathologic evaluation of an autopsied brain from another patient with SCA36. RESULTS: The (GGCCTG)n expansion was found in 18 ataxic patients from 9 families. The age at onset of ataxia was 53.1 ± 3.4 years, with the most frequent symptoms being truncal ataxia (100% of patients), ataxic dysarthria (100%), limb ataxia (93%), and hyperreflexia (79%). Tongue fasciculation and subsequent atrophy were found in 71% of cases, particularly in those of long duration. Skeletal muscle fasciculation and atrophy of the limbs and trunk were found in 57% of cases. Lower motor involvement was confirmed by EMG and muscle biopsy. The neuropathologic study revealed significant cerebellar Purkinje cell degeneration with obvious loss of lower motor neurons. Immunohistochemical analysis showed that NOP56 was localized to the nuclei of various neurons. Cytoplasmic or intranuclear inclusion staining of NOP56, TDP-43, and ataxin-2 was not observed in the remaining neurons. CONCLUSIONS: This is the first description of the unique clinical features of SCA36, a relatively pure cerebellar ataxia with progressive motor neuron involvement. Thus, SCA36 is a disease that stands at the crossroads of SCA and motor neuron disease.
Subject(s)
Brain/pathology , Motor Neurons/pathology , Nerve Degeneration/pathology , Nuclear Proteins/genetics , Spinocerebellar Ataxias/pathology , Age of Onset , Aged , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Nerve Degeneration/genetics , Pedigree , Spinocerebellar Ataxias/genetics , Trinucleotide Repeat ExpansionABSTRACT
BACKGROUND: X-linked Charcot-Marie-Tooth disease (CMTX) is a common inherited axonal or mixed axonal-demyelinating neuropathy. The disease is caused by mutations in the GJB1 gene encoding the gap junction protein connexin32, which is expressed in both Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system. Several reports have described CMTX patients presenting with transient and recurrent central nervous system (CNS) symptoms with transient white matter lesions in the brain. PATIENTS: We describe a man with CMTX who presented with transient CNS symptoms and abnormal cerebral white matter lesions in MRI. He was subjected to a detailed MRI examination using two specialized techniques, diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS). RESULTS: In the early stage of his CNS symptoms, MRS studies revealed reduced N-acetyl-aspartate (NAA) levels in deep white matter, and DTI revealed reduced fractional anisotropy within lesions. Interestingly, these reductions began to recover from day 19 after admission, and follow-up DTI and MRS studies on day 101 revealed a reversal of the abnormalities. CONCLUSION: The findings of reversible reductions in fractional anisotropy and NAA levels in our patient suggest reversible axonal damage associated with deficient oligodendrocyte gap junctions.
Subject(s)
Cerebrum/pathology , Charcot-Marie-Tooth Disease/diagnosis , Diffusion Tensor Imaging , Magnetic Resonance Spectroscopy , Nerve Fibers, Myelinated/pathology , Adult , Charcot-Marie-Tooth Disease/genetics , Charcot-Marie-Tooth Disease/pathology , Humans , MaleABSTRACT
A 78-year-old woman was admitted for severe heat stroke with brain damage. She was unconscious on arrival at the emergency room. Her armpit temperature was 42.0 degrees C and blood pressure was 76/25 mmHg. She was rapidly cooled and given intensive treatment. On magnetic resonance imaging, T1- and T2-weighted images showed no significant signals, but diffusion-weighted images demonstrated localized symmetrical injuries of the cerebellum and thalami. She gradually became conscious, but severe cerebellar ataxia persisted.
Subject(s)
Cerebellar Ataxia/etiology , Heat Stroke/complications , Heat Stroke/diagnosis , Aged , Cerebellum/pathology , Diffusion Magnetic Resonance Imaging , Female , Heat Stroke/pathology , Humans , Thalamic Nuclei/pathologyABSTRACT
We report two patients with spinocerebellar ataxia (SCA) with cranial and spinal motor neuron involvement. They initially presented with cerebellar ataxia, followed by bulbar palsy and limb motor neuron sign. One of the patients had a brother with allied disorder. SCA type 1 (SCA1), SCA3 and SCA6 have been reported to involve the motor neuron system, but they were excluded by DNA analyses in the present two patients. These two patients may form a distinct disease entity among SCAs.
Subject(s)
Bulbar Palsy, Progressive/complications , Motor Neuron Disease/complications , Spinocerebellar Ataxias/complications , Bulbar Palsy, Progressive/diagnosis , DNA/genetics , Electromyography , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Motor Neuron Disease/diagnosis , Muscular Atrophy/complications , Muscular Atrophy/diagnosis , Muscular Atrophy/pathology , Pedigree , Spinocerebellar Ataxias/diagnosis , Spinocerebellar Ataxias/genetics , Tongue/pathologyABSTRACT
RIC-8 was originally found by genetic studies on C. elegans mutants that were resistant to inhibitors of acetylcholinesterase and reported to act in vitro as a guanine nucleotide exchange factor for G protein alpha subunits. However, the physiological role of a mammalian homolog Ric-8A on G protein-coupled receptor signaling in intact cells is largely unknown. We isolated Ric-8A using a yeast two-hybrid system with Galphaq and examined the role of Ric-8A on Gq-mediated signaling. The small interfering RNA of Ric-8A diminished the Gq-coupled receptor-mediated ERK activation and intracellular calcium mobilization in 293T cells. Ric-8A was translocated to the cell membrane in response to the Gq-coupled receptor stimulation. The expression of the myristoylation sequence-conjugated Ric-8A mutant was located in the membranes and shown to enhance the Gq-coupled receptor-mediated ERK activation. Moreover, this enhancement on ERK activation and the guanine nucleotide exchange activity of Ric-8A for Galphaq were inhibited by Gq selective inhibitor YM-254890. These results suggested that Ric-8A potentiates Gq-mediated signal transduction by acting as a novel-type regulator in intact cells.
Subject(s)
GTP-Binding Protein alpha Subunits, Gq-G11/metabolism , Nuclear Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism , Signal Transduction , Animals , Baculoviridae/genetics , Baculoviridae/metabolism , Brain/cytology , Brain/metabolism , Calcium/metabolism , Cell Membrane/metabolism , Cells, Cultured , Cytosol/metabolism , Endothelin-1/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Gene Silencing , Guanine/metabolism , Guanine Nucleotide Exchange Factors , Humans , Mice , Microscopy, Fluorescence , Nuclear Proteins/genetics , Nuclear Proteins/pharmacology , Peptides, Cyclic/metabolism , Peptides, Cyclic/pharmacology , Protein Transport , RNA, Small Interfering/biosynthesis , RNA, Small Interfering/metabolism , Rats , Receptors, G-Protein-Coupled/genetics , Time Factors , Two-Hybrid System TechniquesABSTRACT
Cell migration is a complex phenomenon that is stimulated by chemoattractive factors such as chemokines, a family of ligands for G protein-coupled receptors (GPCRs). In contrast, factors that suppress cell migration, and the mechanism of their action, remain largely unknown. In this study, we show that endothelin, a GPCR ligand, inhibits cell motility in a manner dependent upon signaling through the c-Jun N-terminal kinase (JNK) pathway. We further demonstrate that this effect is dependent upon Src kinase and small GTPases Rac1 and Cdc42. These findings provide new insight into GPCR-mediated regulation of cell migration.
Subject(s)
Endothelins/metabolism , MAP Kinase Kinase 4 , Mitogen-Activated Protein Kinases/metabolism , cdc42 GTP-Binding Protein/metabolism , rac1 GTP-Binding Protein/metabolism , src-Family Kinases/metabolism , Cell Movement/drug effects , Cells, Cultured , Endothelins/pharmacology , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Humans , JNK Mitogen-Activated Protein Kinases , Mitogen-Activated Protein Kinase Kinases/drug effects , Mitogen-Activated Protein Kinase Kinases/genetics , Mitogen-Activated Protein Kinase Kinases/metabolism , Mitogen-Activated Protein Kinases/drug effects , Signal Transduction , cdc42 GTP-Binding Protein/drug effects , rac1 GTP-Binding Protein/drug effects , src-Family Kinases/drug effectsABSTRACT
We previously reported that the alpha1B-adrenergic receptor leads to activation of Rho family small GTPases, and in turn, c-Jun N-terminal kinase (JNK), which results in the inhibition of cell proliferation. Here, we show the involvement of the Rho family guanine nucleotide exchange factor (GEF) Dbl's Big Sister (Dbs) in the signaling pathway. Transfection of a Dbl-homology (DH) and pleckstrin-homology (PH) domain-deficient form of Dbs into cells blocked the alpha1B-adrenergic receptor-induced activation of JNK. Conversely, transfection of an isolated DH domain of Dbs induced JNK activation. Stimulation of the alpha1B-adrenergic receptor enhanced an intrinsic Cdc42-GEF activity of Dbs in a manner dependent on Src family tyrosine kinases. Additionally, DH and PH domain deficient Dbs blocked the receptor-induced inhibition of cell proliferation, while DH domain of Dbs inhibited cell proliferation via the JNK-dependent pathway. Taken together, Dbs may play an important role in the anti-mitogenic JNK pathway downstream of the alpha1B-adrenergic receptor.