Diseases Motor Neuron Disease. Ann Neurol, 63 (4),

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Last updated: August 28, 2019

DiseasesArnold E. S., Ling S. C., et al (2013). ALS-linked TDP-43mutations produce aberrant RNA splicing and adult-onset motor neuron diseasewithout aggregation or loss of nuclear TDP-43.

PNAS, 110(8) 736-745. Amyotrophic lateralsclerosis (ALS) along with frontotemporal lobar degeneration with ubiquitinatedinclusions (FTLD-U) contribute to neurodegenerative diseases. This study investigatedthe effect of mutations to the TDP-43 protein, which has been linked to motorneuron diseases (MNDs). Using generated transgenic mice with a mutation in theTDP-43 scientists were able to track the mutation during the developmentalprocess. At birth, both control and mutant of the TDP-43 were almost indistinguishable. However, after 3 months the mutants beganto show signs of tremors which worsened with age. The TDP-43 mutant did notneed to show aggregation to show symptoms of MNDs revealed by the immunostaining.This research provides a better understanding of loss of function mutations toneuronal pathways and their effects on MNDs.

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 Selective Methods:Generation of transgenic mice, RT-qPCR, immunoblotting, immunohistochemistry, morphometricanalysis, Quantification of motor neurons, animal behavior, electrophysiology,nuclear-cytosolic fractionation, microarray. Gitcho M. A.

, Baloh R. H., et al. (2008).

TDP-43 A315T Mutation inFamiliar Motor Neuron Disease. Ann Neurol,63 (4), 535-538 Neurodegenerative disordersare some of the most physically devastating diseases. These motor neurondiseases (MND) act slowly with affected individuals losing the ability to usecertain appendages, upper body, and /or lower body control and will result indeath. This study used previous works from the TAR DNA-binding protein 43 (TDP43) as an proteopathy. DNA sequencing of TDP 43 exposed a missensemutation, ALA-315-Thr (A-315-T) within exon 6. This alanine residue is criticalsince it has been conserved in humans and distant ancestors.

Of the 1,505subjects that were sequenced, most with a MND showed a mutation with theA-315-T residue. More evidence is needed to continue this experiment, mainly anautopsy of affected subjects. Some MNDs are contributed to frontotemporal lobardegeneration and an autopsy would help to determine this. The discovery of themissense mutation in TDP 43 could provide targets for therapeutic methods inthe future. Selective methods: PCR, DNAsequencing.  Transport Orly Lararov, Gerardo A.Morfini.

, et al. (2007). impairmentsin Fast Axonal Transport and Motor Neuron Deficits in transgenic MiceExpressing Familial Alzheimer’s Disease-Linked Mutant Presenilin 1. The journal of Neuroscience, 27(26),7011-7020. Presenilins (PS1 and PS2)are multipass membrane proteins that regulate “y-secretase”, but have alsoshown to play a role with intracellular trafficking of selected proteins. Mutationsof PS1 and PS2 have been shown to cause familial Alzheimer’s disease (FAD).

 Going on previous data of the motor in thelumbar spinal cord of FAD-linked mutants, PS1 mice showed increasephosphorylation of tau, neurofilaments, and two major cytoskeletal proteins. FAD-linkedmutant mice showed a very large impairment of axonal transport and resulted inimpaired motor performance. The ligation experiments revealed that PS1mutations increased GSK-3 and kinesin-1 transport of proteins. FAD-mutantshowed impairment of anterograde fast axonal transport (FAT) of severalmembrane proteins. Mainly Trk receptor and role in synaptic transmitions,synaptic plasticity. Understanding of the FAD-mutants and PS1 impairments ofFAT may lead to better understanding of early onset Alzheimer’s Diseases. Selected methods: Antibodes,western blot, protein extraction, Rotorod test, Immunohistochemically analysis,Electrophysiological examination.

 Stem Cell and development Di Giorgio F. P., CarrascoM. A.

, et al. (2007). Non-cellautonomous effect of glia on motor neuron in an embryonic stem cell-based ALSmodel. Nat Neurosci, 10(5), 608-614. Amyotrophic lateralsclerosis (ALS) is a motor neuron disease (MND) and progressiveneurodegenerative disease that causes a loss of function in upper and lowermotor neurons which results in death. Most cases of the disease are notgenetically linked, with the exception of a few. From that few that aregenetically linked, most are caused by a dominant mutation in the gene forsuper oxide dismutase (SOD1).

Using embryonic stem cells (ESCs) from non-mutatedand mutated SOD1 gene in mouse development were studied to see the effects ofthe mutation. Immunostaining and green fluorescent proteins showed thedevelopment of the neuron cells. Glial and motor neuron cells were both watchedand grown in close proximity of each other. Those with the SOD1 mutation seemedto be dying around fourteen days.

The effect the SOD1 mutation had changedglial cells to have an independent negative effect on motor neuron cellsurvival. Selective methods:Immunostaining, green fluorescent protein. Cytoskeleton Mishra M., Paunesku T.

, et al. (2007). Gene expression analysisof frontotemporal lobar degeneration of motor neuron disease type with ubiquitinatedinclusions. Acta Neuropathol, 114, 81-94. Frontotemporal degeneration(FTD) are diseases classified on protein deposits/inclusions. Protein missfolding is one of the main causes of dementia related diseases. This studycompares effected frontotemporal lobar degeneration with uninitiated inclusions(FTLD-U), frontotemporal lobar degeneration motor neuron disease(FTLD-MND), andcontrol subjects, using microarray, qRT-PCR, northern blot. qRT-PCR of threegenes that contribute to cytoskeleton proteins/filaments were observed, namelyDNAI1.

The results of the qRT-PCR showed that DNAI1 was expressed three timesmore in FTLD-U than FTLD-MND and controls. Apoptotic factors such as MDM4 andprotein p53 were altered in the FTLD-U and FTL-MND. DNALI1 was shown tointeract with TDP43 which has been shown to cause ubiquitinated inclusions.Further research into the actions of DNALI1 and its interactions are needed.

The genes studied here could be targeted for therapeutic measures.   Selective methods: Northenblot, case studies, RNA extraction, microarray hybrdaiztion, microarray dataanalysis, qRT-PCR, statiscal analysis, PCR and cluster analysis.  Signal Transduction Zhuang B., Su Y. S.

, et al. (2008). Motor Neuron Subtypesthrough Transmembrane Semaphorin6A and PlexinA Signaling.

Neuron, 61(3), 359-372. Dendrites are part ofneurons that extend to reach the axon of neighboring neuron cells for cellsignaling. Although dendrites have many diseases associated with them such asepilepsy and autism not much is not known about how they grow to connect theaxon of adjacent neuron cells.

This study attempts to measure dendriteregulation of growth of cell signaling with FERM, RhoDEF, and pleckstrinhomology domain protein 1 (Farp 1). Scientists made short hairpin RNAs (shRNAs)targeted at Farp 1 and found a deregulation of Farp 1 decreased activity ofFarp1 by 91%.  The shRNAs that targetedFarp 1 showed 39% reduction in length of motor neurons. Both of these resultsshow that Farp 1 is involved in the regulation of neuron length.  To determine whether Farp 1 controls dendritelength two different signaling pathways, they used Sema6A/Plex44 and retinoid pathway. A ColPassay reveals that Farp 1 signaling pathway is directly controls dendritedevelopment.

 Selective methods: RT-PCR,Plasmids, Reverse northern blots, ColP Assay, Ligand production and receptorbinding, In Ovo electroporation and tissue Preparation, In Situ Hybridaztionand immunohistochemistry, Primary Neuronal Cultures and Motor Neuron Analysis Cancer Stich O., Kleer B., et al. (2007). Absence of paraneoplasticantineuronal antibodies in ssera of 145 patients with motor neuron disease. J Neurol Nuerosurg Psychiatry, 78(8), 883-885.

 Paraneoplastic neurologicalsyndromes (PNS) from cancer are believed to be correlated with autoimmuneeffected neuronal tissues. This studies aims to identify if there is anaccumulation of paraneoplastic antineuronal antibodies (ANAbs) in patients withmotor neuron disease (MND). 222 patients with MNDs were evaluated and 145 ofthose patients were chosen based on El Escorial criteria. An ELISA wasperformed on the chosen 145 patients to determine the frequency of ANAbs inpatients with MNDs. From patients that were previously diagnosed PNS, 21 hadhigh antineuronal antigen reactivity. None of the other MND patients showed ahigh antineuronal antigen reactivity. From the six ELISAs preformed none of thepatients showed to have a high frequency antineuronal antigen. These resultsdemonstrate that it would not be necessary to screen patients with MNDs to forANAbs as the only ones to be detected were ones with previously occurring PNS.

 Selective methods: ELISA,immunochemistry,  Metabolism Haramati S., Chapnik E., et al.

(2010). miRNA malfunction causesspinal motor neuron diseases. PNAS, 107(29),13111-13116. One of the most heavilyregulated posttranscriptional processes is micro-RNA (miRNA), due to theirabundance and their regulation of downstream targets. This study looks atdefective RNA metabolism and its ability to have ALS pathogenic traits.Deregulation of miRNAs could affect RNA metabolism.

They performed a lose itexperiment by deleting the Dicer1 gene, which is known to regulate miRNA. Usingan electromyography (EMG) the mice with deleted Dicer1 gene showed frequentfibrillation. Fibrillation has been identified in animals with progressivelocomotive deterioration. Looking at the motor neurons (MNs) of the spinal cordof deleted Dicer1 mice showed a significant decrease in number of MNs. Thisstudy shows the importance of miRNAs and their function of regulation in motorneuron development and RNA metabolism. This could be target for treatment ofmotor neurological diseases.  Selective methods: Lose itexperiment, Microarray, Electromyography, spinal cord histology. Hanada, T.

, Weitzer S., et al. (2013) The RNA kinaseCLP1 links tRNA metabolism to progressive motor neuron loss. Nature, 495(7442): 474-480.  One of the known functionsof Clp1 is to be a RNA kinase in mammals and archaebacterial; the other functionof Clp1 was not known. To find out the function they generated transgenic miceto have a mutant Clp1 and called it Clp1 (K/K).

All Clp1 (K/K) expressednonfunctional neuro muscular junctions in the diaphragm that then causedrespiratory failure and lead to neonatal death. They successfully gothomozygous Clp1 (K/K) that were able to survive after birth, but exhibited aloss in motor functions. The viable Clp1 (K/K) spinal cords were to tested andfound a buildup tyrosine tRNA fragments. tRNA fragments were also linked tooxidative stress and activating p53 tumor suppressor pathway.

By deactivatingthe p53 pathway and reducing the oxidative stresses they were able to recoverthe function of the motor neurons. The tRNA processing helps neural metabolism. Selective methods:generation of transgenic mice, phenotyping, pre-tRNA splicing, Northern blot,identification of tyrosine tRNA fragments.

  Membrane structure and function  Laird F.M., Farah M. H., et al. (2008). Motor Neuron Disease Occurring in Mutant DynactinMouse Model Is Characterized by Defects in Vesicular Trafficking. The Journal of Neuroscience, 28(9),1997-2005.

 Familial amyotrophic lateralsclerosis (ALS) has been linked to a mutation in p150 glued of the dynactin complex. Dynactin p150 glued is part of a multiprotein complex that separates withdynein and is required for retrograde transport of vesicles on the membrane. Thisstudy generated transgenic mice with a mutation in the p150 glued gene and traced the cells with immunostainingprocedures. Immunostaining revealed a very large accumulation of membranevesicle structures at five months of age.

This research is important because itshows that a p150 mutation results in a buildup of vesicles that causes axonalswelling. The results also show that cell counts diminished and there is a possibility that the neuroncell been autophagic characteristics. This study proves that the pl150 glued mutation can contribute to neuron cell death.  Selective methods:Generation of transgenic mice, SDS-PAGE, Immunoblotting, immunocytochemistry, electrography,muscle histology, neuron histology, immunofluorescence.

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