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Primary lateral sclerosis

Amrutha Swaminathan, Marilou Bouffard, Meijiang Liao, Sarah Ryan, Janis Bennion Callister, Stuart M Pickering-Brown, Gary Alan Barclay Armstrong, Pierre Drapeau
Large expansions of hexanucleotide GGGGCC (G4C2) repeats (hundreds to thousands) in the first intron of the chromosome 9 open reading frame 72 (C9orf72) locus are the strongest known genetic factor associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS/FTLD). Different hypotheses exist about the underlying disease mechanism including loss-of-function by haploinsufficiency, toxicity arising as a result of RNA or dipeptide repeats (DPRs). Five different DPRs are produced by repeat-associated non-ATG-initiated (RAN) translation of the G4C2 repeats...
March 8, 2018: Human Molecular Genetics
João R Gomes, Inês Cabrito, Hugo R Soares, Susete Costelha, Anabela Teixeira, Angela Wittelsberger, Catelijne Stortelers, Peter Vanlandschoot, Maria J Saraiva
Transthyretin (TTR) is a transport protein of retinol and thyroxine in serum and cerebrospinal fluid (CSF), which is mainly secreted in liver and choroid plexus, and in smaller amounts in other cells throughout the body. The exact role of TTR and its specific expression in Central Nervous System (CNS) remains understudied. We investigated TTR expression and metabolism in CNS, through the intranasal and intracerebroventricular delivery of a specific anti-TTR Nanobody to the brain, unveiling Nanobody pharmacokinetics to the CNS...
March 12, 2018: Journal of Neurochemistry
Nicholas J Kramer, Michael S Haney, David W Morgens, Ana Jovičić, Julien Couthouis, Amy Li, James Ousey, Rosanna Ma, Gregor Bieri, C Kimberly Tsui, Yingxiao Shi, Nicholas T Hertz, Marc Tessier-Lavigne, Justin K Ichida, Michael C Bassik, Aaron D Gitler
Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons...
March 5, 2018: Nature Genetics
Yasuhiro Hijikata, Masahisa Katsuno, Keisuke Suzuki, Atsushi Hashizume, Amane Araki, Shinichiro Yamada, Tomonori Inagaki, Daisuke Ito, Akihiro Hirakawa, Fumie Kinoshita, Masahiko Gosho, Gen Sobue
BACKGROUND: Although spinal and bulbar muscular atrophy (SBMA) has been classified as a motor neuron disease, several reports have indicated the primary involvement of skeletal muscle in the pathogenesis of this devastating disease. Recent studies reported decreased intramuscular creatine levels in skeletal muscles in both patients with SBMA and transgenic mouse models of SBMA, which appears to contribute to muscle weakness. OBJECTIVE: The present study aimed to examine the efficacy and safety of oral creatine supplementation to improve motor function in patients with SBMA...
March 5, 2018: JMIR Research Protocols
Antonio Vallarola, Francesca Sironi, Massimo Tortarolo, Noemi Gatto, Roberta De Gioia, Laura Pasetto, Massimiliano De Paola, Alessandro Mariani, Supurna Ghosh, Richard Watson, Andreas Kalmes, Valentina Bonetto, Caterina Bendotti
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects the motor neuromuscular system leading to complete paralysis and premature death. The multifactorial nature of ALS that involves both cell-autonomous and non-cell-autonomous processes contributes to the lack of effective therapies, usually targeted to a single pathogenic mechanism. RNS60, an experimental drug containing oxygenated nanobubbles generated by modified Taylor-Couette-Poiseuille flow with elevated oxygen pressure, has shown anti-inflammatory and neuroprotective properties in different experimental paradigms...
March 1, 2018: Journal of Neuroinflammation
Ross Ferguson, Vasanta Subramanian
Angiogenin (ANG), a member of the RNase superfamily (also known as RNase 5) has neurotrophic, neuroprotective and angiogenic activities. Recently it has also been shown to be important in stem cell homeostasis. Mutations in ANG are associated with neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and Fronto-temporal dementia (FTD). ANG is a secreted protein which is taken up by cells and translocated to the nucleus. However, the import pathway/s through which ANG is taken up is/are still largely unclear...
2018: PloS One
Layla T Ghaffari, Alexander Starr, Andrew T Nelson, Rita Sattler
Neurological diseases, including dementias such as Alzheimer's disease (AD) and fronto-temporal dementia (FTD) and degenerative motor neuron diseases such as amyotrophic lateral sclerosis (ALS), are responsible for an increasing fraction of worldwide fatalities. Researching these heterogeneous diseases requires models that endogenously express the full array of genetic and epigenetic factors which may influence disease development in both familial and sporadic patients. Here, we discuss the two primary methods of developing patient-derived neurons and glia to model neurodegenerative disease: reprogramming somatic cells into induced pluripotent stem cells (iPSCs), which are differentiated into neurons or glial cells, or directly converting (DC) somatic cells into neurons (iNeurons) or glial cells...
2018: Frontiers in Neuroscience
Flora M Hammond, William Sauve, Fred Ledon, Charles Davis, Andrea E Formella
BACKGROUND: Dextromethorphan 20mg /quinidine 10mg (DM/Q) was approved to treat pseudobulbar affect (PBA) based upon phase 3 trials conducted in participants with amyotrophic lateral sclerosis or multiple sclerosis. PRISM II evaluated DM/Q effectiveness, safety and tolerability for PBA following stroke, dementia or traumatic brain injury (TBI). OBJECTIVE: To report results from the TBI cohort of PRISM II, including a TBI-specific functional scale. DESIGN: Open-label trial evaluating twice daily DM/Q over 90 days...
February 22, 2018: PM & R: the Journal of Injury, Function, and Rehabilitation
Kaori Sugiyama, Kohichi Tanaka
Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disorder characterized by the selective loss of motor neurons. The precise mechanisms that cause the selective death of motor neurons remain unclear, but a growing body of evidence suggests that glutamate-mediated excitotoxicity has been considered to play an important role in the mechanisms of motor neuron degeneration in ALS. Reductions in glutamate transporter GLT1 have been reported in animal models of ALS and the motor cortex and spinal cord of ALS patients...
February 16, 2018: Biochemical and Biophysical Research Communications
Enrica Bersano, Maria Francesca Sarnelli, Valentina Solara, Fabiola De Marchi, Gian Mauro Sacchetti, Alessandro Stecco, Lucia Corrado, Sandra D'alfonso, Roberto Cantello, Letizia Mazzini
We describe a 64-year-old woman, suffering from late-onset obsessive-compulsive disorder (OCD) from the age of 57, who developed dysarthria and dysphagia, spastic diplegic, and proximal muscles weakness. Needle electromyography showed no active denervation. Neuropsychological evaluation showed intact cognitive functioning. We diagnosed upper motor neuron disease (MND), with no known genetic correlates. Brain magnetic resonance (MRI) detected bilateral hippocampal atrophy with sclerosis of right hippocampus...
February 16, 2018: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Blandine Madji Hounoum, Hélène Blasco, Emmanuelle Coque, Patrick Vourc'h, Patrick Emond, Philippe Corcia, Christian R Andres, Cédric Raoul, Sylvie Mavel
Glutamate-induced excitotoxicity is considered as one of the major pathophysiological factors of motoneuron death in amyotrophic lateral sclerosis and other motoneuron diseases. In order to expand our knowledge on mechanisms of glutamate-induced excitotoxicity, the present study proposes to determine the metabolic consequences of glutamate and astrocytes in primary enriched motoneuron culture. Using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS), we showed that the presence of astrocytes and glutamate profoundly modified the metabolic profile of motoneurons...
February 12, 2018: Molecular Neurobiology
Shizuka Takaku, Hideji Yako, Naoko Niimi, Tomoyo Akamine, Daiji Kawanami, Kazunori Utsunomiya, Kazunori Sango
Co-culture models of neurons and Schwann cells have been utilized for the study of myelination and demyelination in the peripheral nervous system; in most of the previous studies, however, these cells were obtained by primary culture with embryonic or neonatal animals. A spontaneously immortalized Schwann cell line IFRS1 from long-term cultures of adult Fischer rat peripheral nerves has been shown to retain fundamental ability to myelinate neurites in co-cultures with adult rat dorsal root ganglion neurons and nerve growth factor-primed PC12 cells...
February 12, 2018: Histochemistry and Cell Biology
Sonam Parakh, Cyril J Jagaraj, Marta Vidal, Audrey M G Ragagnin, Emma R Perri, Anna Konopka, Reka Toth, Jasmin Galper, Ian P Blair, Colleen J Thomas, Adam K Walker, Shu Yang, Damian M Spencer, Julie D Atkin
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder and mutations in superoxide dismutase1 (SOD1) account for 20% of familial ALS cases. The aetiology of ALS remains unclear, but protein misfolding, endoplasmic reticulum (ER) stress and neuronal apoptosis are implicated. We previously established that protein disulphide isomerase (PDIA1) is protective against ER stress and apoptosis in neuronal cells expressing mutant SOD1, recently mutations in PDIA1 and related PDI family member endoplasmic reticulum protein 57 (ERp57/PDIA), were associated with ALS...
February 1, 2018: Human Molecular Genetics
Sarah A Morrow, Heather Rosehart, Alp Sener, Blayne Welk
Bladder dysfunction is common in persons with MS (PwMS), often due to detrusor muscle overactivity. Anticholinergic medications are considered the first line treatment for bladder dysfunction and are known to worsen cognition in healthy older adults and in persons with dementia. Yet, it is not known if these medications have the same effect on PwMS. Thus, the Objective of this prospective matched-cohort study was to determine if anticholinergic medications affect objective measures of cognition in PwMS. We recruited PwMS starting either oxybutynin or tolterodine (cases)...
February 15, 2018: Journal of the Neurological Sciences
Fiona Limanaqi, Stefano Gambardella, Gloria Lazzeri, Michela Ferrucci, Stefano Ruggieri, Francesco Fornai
Amyotrophic Lateral Sclerosis (ALS) is a fast progressive neurodegenerative disease characterized by muscle denervation, weakening and atrophy, which eventually culminates into death, mainly due to respiratory failure. The traditional view of ALS as a disorder affecting selectively motor neurons throughout the central nervous system has been progressively dispelled by innumerous lines of evidence indicating that other cells but motor neurons may be affected as well. Remarkably, this disorder is not limited to the motor system but rather configures as a systemic disease yielding a plethora of clinical signs...
December 1, 2017: Archives Italiennes de Biologie
Federico Verde, Kelly Del Tredici, Heiko Braak, Albert Ludolph
Amyotrophic lateral sclerosis (ALS) is traditionally considered a disease affecting exclusively motor neurons. However, much evidence points towards additional involvement of brain systems other than the motor. As much as half of ALS patients display cognitive-behavioral disturbances. ALS shares with a considerable proportion of FTD cases the same neuropathological substrate, namely, inclusions of abnormally phosphorylated protein TDP-43 (pTDP-43). In analogy with pathological staging systems elaborated in the past decades for Alzheimer's disease (AD) and Parkinson's disease (PD), a model of staging of pTDP-43 pathology in sporadic ALS (sALS) has been recently proposed...
December 1, 2017: Archives Italiennes de Biologie
Jinsy A Andrews, Merit E Cudkowicz, Orla Hardiman, Lisa Meng, Amy Bian, Jacqueline Lee, Andrew A Wolff, Fady I Malik, Jeremy M Shefner
OBJECTIVE: To assess the efficacy of tirasemtiv, a fast skeletal muscle troponin activator, vs. placebo on respiratory function and other functional measures in patients with amyotrophic lateral sclerosis (ALS). This study was designed to confirm and extend results from a large phase IIb trial and maximize tolerability with a slower dose escalation. METHODS: VITALITY-ALS (NCT02496767) was a multinational, double-blind, randomized, placebo-controlled, parallel-group study in ALS patients...
February 6, 2018: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Tom Burke, Orla Hardiman, Marta Pinto-Grau, Katie Lonergan, Mark Heverin, Katy Tobin, Anthony Staines, Miriam Galvin, Niall Pender
OBJECTIVE: Caregiver burden is a recognised consequence of caring for a patient with neurodegeneration. Amyotrophic lateral sclerosis (ALS) differs from other neurodegenerations by its rapid progression and impairment of motor, cognitive, and behavioural function, which contribute to caregiver burden. However, longitudinal factors that determine the extent of caregiver burden, and in particular the impact of psychological distress among caregivers, have not been fully established. METHODS: Patients with ALS (n = 85) and their primary caregivers (n = 85) completed three serial evaluations...
February 2, 2018: Journal of Neurology
Philippe Codron, Julien Cassereau, Patrick Vourc'h, Charlotte Veyrat-Durebex, Hélène Blasco, Selma Kane, Vincent Procaccio, Franck Letournel, Christophe Verny, Guy Lenears, Pascal Reynier, Arnaud Chevrollier
OBJECTIVE: Sporadic amyotrophic lateral sclerosis (sALS) is a fatal neurodegenerative disorder affecting upper and lower motor neurons. In view of the heterogeneous presentation of the disease, one of the current challenges is to identify diagnostic and prognostic markers in order to diagnose sALS at early stage and to stratify patients in trials. In this study, we sought to identify cytological hallmarks of sALS in patient-derived fibroblasts with the aim of finding new clinical-related markers of the disease...
January 31, 2018: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Azadeh Kia, Kevin McAvoy, Karthik Krishnamurthy, Davide Trotti, Piera Pasinelli
Mutations in fused in sarcoma (FUS) are linked to amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease affecting both upper and lower motor neurons. While it is established that astrocytes contribute to the death of motor neurons in ALS, the specific contribution of mutant FUS (mutFUS) through astrocytes has not yet been studied. Here, we used primary astrocytes expressing a N-terminally GFP tagged R521G mutant or wild-type FUS (WTFUS) and show that mutFUS-expressing astrocytes undergo astrogliosis, damage co-cultured motor neurons via activation of an inflammatory response and produce conditioned medium (ACM) that is toxic to motor neurons in isolation...
January 30, 2018: Glia
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