Exercise attenuates polyglutamine-mediated neuromuscular degeneration in a mouse model of spinal and bulbar muscular atrophy.

BACKGROUND: Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by the expansion of trinucleotide cytosine-adenine-guanine (CAG) repeats, which encodes a polyglutamine (polyQ) tract in the androgen receptor (AR) gene. Recent evidence suggests that, in addition to motor neuron degeneration, defective skeletal muscles are also the primary contributors to the pathogenesis in SBMA. While benefits of physical exercise have been suggested in SBMA, underlying mechanism remains elusive. METHODS: We investigated the effect of running exercise in a transgenic mouse model of SBMA carrying human AR with 97 expanded CAGs (AR97Q). We assigned AR97Q mice to exercise and sedentary control groups, and mice in the exercise group received 1-h forced running wheel (5 m/min) 5 days a week for 4 weeks during the early stage of the disease. Motor function (grip strength and rotarod performance) and survival of each group were analysed, and histopathological and biological features in skeletal muscles and motor neurons were evaluated. RESULTS: AR97Q mice in the exercise group showed improvement in motor function (~40% and ~50% increase in grip strength and rotarod performance, respectively, P < 0.05) and survival (median survival 23.6 vs. 16.7 weeks, P < 0.05) with amelioration of neuronal and muscular histopathology (~1.4-fold and ~2.8-fold increase in motor neuron and muscle fibre size, respectively, P < 0.001) compared to those in the sedentary group. Nuclear accumulation of polyQ-expanded AR in skeletal muscles and motor neurons was suppressed in the mice with exercise compared to the sedentary mice (~50% and ~30% reduction in 1C2-positive cells in skeletal muscles and motor neurons, respectively, P < 0.05). We found that the exercise activated 5'-adenosine monophosphate-activated protein kinase (AMPK) signalling and inhibited mammalian target of rapamycin pathway that regulates protein synthesis in skeletal muscles of SBMA mice. Pharmacological activation of AMPK inhibited protein synthesis and reduced polyQ-expanded AR proteins in C2C12 muscle cells. CONCLUSIONS: Our findings suggest the therapeutic potential of exercise-induced effect via AMPK activation in SBMA.

Acute bilateral hypotropia and esotropia complex as first manifestation of multiple sclerosis: a case report.

A 21-year-old Japanese woman presented with sudden eye movement disorders. An ophthalmic examination revealed bilateral hypotropia and esotropia complex. Brain magnetic resonance imaging revealed abnormal signals in the posterior and medial part of the lower pontine tegmentum (including periventricular and subcortical white matter) that were suggestive of demyelination. A cerebrospinal fluid test was positive for oligoclonal bands. She was subsequently diagnosed with multiple sclerosis and was administered intravenous methylprednisolone and oral dimethyl fumarate, with complete recovery from hypotropia and esotropia after two months. Bilateral hypotropia and esotropia are important clinical signs for the accurate diagnosis of multiple sclerosis.

Dysregulation of Aldh1a2 underlies motor neuron degeneration in spinal muscular atrophy.

Lower motor neuron degeneration is the pathological hallmark of spinal muscular atrophy (SMA), a hereditary motor neuron disease caused by loss of the SMN1 gene and the resulting deficiency of ubiquitously expressed SMN protein. The molecular mechanisms underlying motor neuron degeneration, however, remain elusive. To clarify the cell-autonomous defect in developmental processes, we here performed transcriptome analyses of isolated embryonic motor neurons of SMA model mice to explore mechanisms of dysregulation of cell-type-specific gene expression. Of 12 identified genes that were differentially expressed between the SMA and control motor neurons, we focused on Aldh1a2, an essential gene for lower motor neuron development. In primary spinal motor neuron cultures, knockdown of Aldh1a2 led to the formation of axonal spheroids and neurodegeneration, reminiscent of the histopathological changes observed in human and animal cellular models. Conversely, Aldh1a2 rescued these pathological features in spinal motor neurons derived from SMA mouse embryos. Our findings suggest that developmental defects due to Aldh1a2 dysregulation enhances lower motor neuron vulnerability in SMA.

α-Synuclein V15A Variant in Familial Parkinson's Disease Exhibits a Weaker Lipid-Binding Property.

BACKGROUND: The α-Synuclein (α-Syn) V15A variant has been found in two Caucasian families with Parkinson's disease (PD). However, the significance of this missense variant remained unclear. OBJECTIVE: We sought to elucidate whether V15A could increase aggregation or change phospholipid affinity. METHODS: A sequencing analysis for the SNCA encoding α-Syn from 875 patients with PD and 324 control subjects was performed. Comparing with known pathogenic missense variants of α-Syn, A30P, and A53T, we analyzed the effects of V15A on binding to phospholipid membrane, self-aggregation, and seed-dependent aggregation in cultured cells. RESULTS: Genetic screening identified SNCA c.44 T>C (p.V15A) from two Japanese PD families. The missense variant V15A was extremely rare in several public databases and predicted as pathogenic using in silico tools. The amplification activity of α-Syn V15A fibrils was stronger than that of wild-type α-Syn fibrils. CONCLUSIONS: The discovery of the V15A variant from Japanese families reinforces the possibility that the V15A variant may be a causative variant for developing PD. V15A had a reduced affinity for phospholipids and increased propagation activity compared with wild-type. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Mid1 is associated with androgen-dependent axonal vulnerability of motor neurons in spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset hereditary neurodegenerative disease caused by the expansions of CAG repeats in the androgen receptor (AR) gene. Androgen-dependent nuclear accumulation of pathogenic AR protein causes degeneration of lower motor neurons, leading to progressive muscle weakness and atrophy. While the successful induction of SBMA-like pathology has been achieved in mouse models, mechanisms underlying motor neuron vulnerability remain unclear. In the present study, we performed a transcriptome-based screening for genes expressed exclusively in motor neurons and dysregulated in the spinal cord of SBMA mice. We found upregulation of Mid1 encoding a microtubule-associated RNA binding protein which facilitates the translation of CAG-expanded mRNAs. Based on the finding that lower motor neurons begin expressing Mid1 during embryonic stages, we developed an organotypic slice culture system of the spinal cord obtained from SBMA mouse fetuses to study the pathogenic role of Mid1 in SBMA motor neurons. Impairment of axonal regeneration arose in the spinal cord culture in SBMA mice in an androgen-dependent manner, but not in mice with non-CAG-expanded AR, and was either exacerbated or ameliorated by Mid1 overexpression or knockdown, respectively. Hence, an early Mid1 expression confers vulnerability to motor neurons, at least by inducing axonogenesis defects, in SBMA.

Nucleic Acid-Based Therapeutic Approach for Spinal and Bulbar Muscular Atrophy and Related Neurological Disorders.

The recent advances in nucleic acid therapeutics demonstrate the potential to treat hereditary neurological disorders by targeting their causative genes. Spinal and bulbar muscular atrophy (SBMA) is an X-linked and adult-onset neurodegenerative disorder caused by the expansion of trinucleotide cytosine-adenine-guanine repeats, which encodes a polyglutamine tract in the androgen receptor gene. SBMA belongs to the family of polyglutamine diseases, in which the use of nucleic acids for silencing a disease-causing gene, such as antisense oligonucleotides and small interfering RNAs, has been intensively studied in animal models and clinical trials. A unique feature of SBMA is that both motor neuron and skeletal muscle pathology contribute to disease manifestations, including progressive muscle weakness and atrophy. As both motor neurons and skeletal muscles can be therapeutic targets in SBMA, nucleic acid-based approaches for other motor neuron diseases and myopathies may further lead to the development of a treatment for SBMA. Here, we review studies of nucleic acid-based therapeutic approaches in SBMA and related neurological disorders and discuss current limitations and perspectives to apply these approaches to patients with SBMA.

Selective suppression of polyglutamine-expanded protein by lipid nanoparticle-delivered siRNA targeting CAG expansions in the mouse CNS.

Polyglutamine (polyQ) diseases are inherited neurodegenerative disorders caused by expansion of cytosine-adenine-guanine (CAG)-trinucleotide repeats in causative genes. These diseases include spinal and bulbar muscular atrophy (SBMA), Huntington's disease, dentatorubral-pallidoluysian atrophy, and spinocerebellar ataxias. Targeting expanded CAG repeats is a common therapeutic approach to polyQ diseases, but concomitant silencing of genes with normal CAG repeats may lead to toxicity. Previous studies have shown that CAG repeat-targeting small interfering RNA duplexes (CAG-siRNAs) have the potential to selectively suppress mutant proteins in in vitro cell models of polyQ diseases. However, in vivo application of these siRNAs has not yet been investigated. In this study, we demonstrate that an unlocked nucleic acid (UNA)-modified CAG-siRNA shows high selectivity for polyQ-expanded androgen receptor (AR) inhibition in in vitro cell models and that lipid nanoparticle (LNP)-mediated delivery of the CAG-siRNA selectively suppresses mutant AR in the central nervous system of an SBMA mouse model. In addition, a subcutaneous injection of the LNP-delivered CAG-siRNA efficiently suppresses mutant AR in the skeletal muscle of the SBMA mouse model. These results support the therapeutic potential of LNP-delivered UNA-modified CAG-siRNAs for selective suppression of mutant proteins in SBMA and other polyQ diseases.

[Nonstenotic Carotid Plaque in Patients with Anterior Circulation Embolic Stroke of Undetermined Source].

Characteristics of nonstenotic (<50%) carotid plaque in embolic stroke of undetermined source (ESUS) are unclear. This study aimed to clarify the size and properties of carotid plaque in patients with ESUS. We retrospectively analyzed the results of carotid ultrasonography in 17 consecutive patients with anterior circulation ESUS and compared the size and morphology of carotid plaque on the ipsilateral and contralateral sides of the stroke lesion. The mean plaque thickness did not significantly differ between both sides (2.13 vs 1.86 mm, p = 0.54), but the mean noncalcified plaque thickness was greater on the ipsilateral side than on the contralateral side (1.15 vs 0.23mm, p = 0.025). Noncalcified plaque with thickness≥2.5mm was observed on the ipsilateral side in five of 17 patients, but not on the contralateral side, suggesting that noncalcified plaque with thickness≥2.5mm is a potential source of ESUS. (Received January 29, 2018; Accepted July 21, 2018; Published November 1, 2018).

Subacute cerebellar ataxia with amphiphysin antibody developing in a patient with follicular thyroid adenoma: a case report.

The patient was a 61-year-old woman with thyroid enlargement since her 20s. She began to fall down repeatedly towards the end of June 2015. She was admitted to our hospital in the middle of August because of difficulty in walking. Upon admission, she presented with neck tremor and was unable to maintain a sitting position due to ataxia of the trunk and limbs. We studied serum anti-neuronal antibodies and obtained a positive result for anti-amphiphysin antibody (AMPH-Ab). Cerebrospinal fluid analysis revealed elevated protein levels and IgG index. Other than the thyroid mass, a tumor was not detected. The resected thyroid specimen showed follicular adenoma. After performing immunotherapies, the cerebrospinal fluid protein levels and IgG index decreased, and her ataxia did not progress. When subacute cerebellar ataxia is suspected, studying AMPH-Ab should be considered.

Trousseau's Syndrome due to Anaplastic Thyroid Carcinoma Presenting with Multiple Ischemic Strokes.

Trousseau's syndrome is characterized by a cerebral or systemic thromboembolism caused by coagulation abnormalities in malignancy. We herein report a case of multiple ischemic strokes as the initial manifestation of anaplastic thyroid carcinoma (ATC). An 86-year-old man was admitted to our hospital due to a sudden-onset weakness of the left limbs. Brain magnetic resonance imaging revealed multiple ischemic lesions in the right middle cerebral artery territory and a mass in the left frontal lobe. Computed tomography revealed a thyroid mass and multiple lung tumors. A diagnosis of ATC was confirmed by a thyroid biopsy. Our case indicates that ATC should be considered as a cause of Trousseau's syndrome.

Elderly-onset familial myasthenia gravis in two siblings.

Myasthenia gravis (MG) occasionally occurs in a family, but elderly-onset (≥65 years) familial MG has been rarely reported. We here report the case of two siblings with elderly-onset MG (mean onset age: 72.5 years) and present the human leukocyte antigen (HLA) profiles (HLA-A, -B, -DR) of their family. Both patients developed generalized MG with elevated serum acetylcholine receptor antibody titers at their seventies. Of six siblings, the two patients and one unaffected sibling shared the same HLA haplotypes. Our study indicates that elderly-onset MG can occur in a family and that familial occurrence of MG may be related to certain HLA alleles.

[Aggregatibacter segnis endocarditis mimicking antineutrophil cytoplasmic antibody-associated vasculitis presenting with cerebral hemorrhage: a case report].

A 56-year-old man who underwent a tooth extraction in the previous year presented with weakness of the right upper extremity. Brain CT and MRI scans showed subcortical hemorrhage in the left frontal lobe. His body temperature was 37.5°C. Blood examination revealed anemia, elevated levels of C-reactive protein, and a positive result for PR3-ANCA. Aggregatibacter segnis was identified in the incubated blood cultures, and transesophageal echocardiograms showed infectious growth in the anterior mitral leaflet. He was diagnosed with infectious endocarditis. After treatment with ceftriaxione, the clinical symptoms were improved. We concluded that infectious endocarditis caused cerebral hemorrhage and that the positive result for PR3-ANCA was a false positive. Infectious endocarditis can mimic ANCA-associated vasculitis. When ANCA-associated vasculitis is suspected, infectious endocarditis must be ruled out.