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Essential Trans-synaptic Nonviability of Individual Neurons Characterized by Dysfunctional Neurofilament Aggregation in Amyotrophic Lateral Sclerosis
Lawrence M. Agius MD
International Journal of Molecular Medicine and Advance Sciences , 2011,
Abstract: Amyotrophic lateral sclerosis would constitute a system complex of heightened neuronal susceptibility that is dependent on skeletal myofiber participation towards further progression of such neuronal injury. Indeed, a simple concept of neurofilament disorganization and abnormal protein trafficking might implicate systems of direct and indirect consequence in inducing both myofiber denervation atrophy on a selective axonal basis of involvement and also a possible pathway of susceptibility towards further intraneuronal disorganization. Indeed, in terms of neuropathologic lesions such as neurofilament skeins and axonal spheroids in a complex setting of aggregation and inclusion bodies in the perikaryon, one might perhaps strictly recognize skeletal myofiber atrophy as a central target of pathology of motoneuron injury in a context however of further induced injury to such motoneurons as resulting from active myofiber atrophy. In simple terms, individual skeletal myofibers that atrophy on an individual axonal basis of injury would constitute a main mechanism for further self-propagation of progressive injury to the supplying axon. Indeed, amyotrophic lateral sclerosis would appear a disease process with active overcompensatory neuronal attempts at recovery further contributing to the disease activity.
Analysis of Novel NEFL mRNA Targeting microRNAs in Amyotrophic Lateral Sclerosis  [PDF]
Muhammad Ishtiaq, Danae Campos-Melo, Kathryn Volkening, Michael J. Strong
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0085653
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by progressive motor neuron degeneration and neurofilament aggregate formation. Spinal motor neurons in ALS also show a selective suppression in the levels of low molecular weight neurofilament (NEFL) mRNA. We have been interested in investigating the role of microRNAs (miRNAs) in NEFL transcript stability. MiRNAs are small, 20–25 nucleotide, non-coding RNAs that act as post-transcriptional gene regulators by targeting the 3′ untranslated region (3′UTR) of mRNA resulting in mRNA decay or translational silencing. In this study, we characterized putative novel miRNAs from a small RNA library derived from control and sporadic ALS (sALS) spinal cords. We detected 80 putative novel miRNAs, 24 of which have miRNA response elements (MREs) within the NEFL mRNA 3′UTR. From this group, we determined by real-time PCR that 10 miRNAs were differentially expressed in sALS compared to controls. Functional analysis by reporter gene assay and relative quantitative RT-PCR showed that two novel miRNAs, miR-b1336 and miR-b2403, were downregulated in ALS spinal cord and that both stabilize NEFL mRNA. We confirmed the direct effect of these latter miRNAs using anit-miR-b1336 and anti-miR-b2403. These results demonstrate that the expression of two miRNAs (miRNAs miR-b1336 and miR-b2403) whose effect is to stabilize NEFL mRNA are down regulated in ALS, the net effect of which is predicted to contribute directly to the loss of NEFL steady state mRNA which is pathognomic of spinal motor neurons in ALS.
NG2 cells response to axonal alteration in the spinal cord white matter in mice with genetic disruption of neurofilament light subunit expression
Ya Wu, Ya Tang, Zhi Xiao, Zhen Bao, Bei He
Molecular Neurodegeneration , 2008, DOI: 10.1186/1750-1326-3-18
Abstract: In the early neuropathological development stage, our study showed that the diameter of axons of upper motor neurons of NFL-/- mice decreased significantly while the thickness of their myelin sheath increased remarkably. Although there was an obvious morphological distortion in axons with occasionally partial demyelination, no obvious changes in expression of myelin proteins was detected. Parallel to these changes in the axons and their myelination, the processes of NG2 cells were disconnected from the nodes of Ranvier and extended further, suggesting that these cells in the spinal cord white matter could sense the alteration in axonal contents caused by disruption of NFL expression before astrocytic and microglial activation.The structural configuration determined by the NFL gene may be important for maintenance of normal morphology of myelinated axons. The NG2 cells might serve as an early sensor for the delivery of information from impaired neurons to the local environment.Neurodegenerative diseases are the main causes for disability, dementia, and death in elderly people. Two common signs of neurodegenerative diseases observed from clinically characterized autopsy tissues at the terminal stage of the diseases are neuronal cell death and glial cell activation. However, the causative relations between these two phenomena are still not fully understood, especially at the early stage of neuropathogenesis.Previous studies have reported that abnormal neurofilament aggregates are often associated with decreases in the level of NFL mRNA, for instance, more than 70% downregulation of NFL mRNA was detected in degenerating neurons of amyotrophic lateral sclerosis (ALS) [1,2]. Therefore, in our previous study, we adopted a mouse model for ALS. In this model, neurodegeneration is initiated in neurons after disruption of NFL expression. The NFL-/- mice will develop abnormal protein accumulation in neuronal perikarya and proximal axons, a common phenomenon in neurodegenerative
Oxaliplatin-induced loss of phosphorylated heavy neurofilament subunit neuronal immunoreactivity in rat DRG tissue
Stephen MF Jamieson, Joshuan Subramaniam, Johnson J Liu, Nancy N Jong, Virginia Ip, Bronwen Connor, Mark J McKeage
Molecular Pain , 2009, DOI: 10.1186/1744-8069-5-66
Abstract: After treatment with oxaliplatin, phosphorylated neurofilament heavy subunit (pNF-H) immunoreactivity was reduced in neuronal cell bodies, but unchanged in nerve fibres, of the L5 DRG. Morphometric analysis confirmed significant changes in the number (-75%; P < 0.0002) and size (-45%; P < 0.0001) of pNF-H-immunoreactive neurons after oxaliplatin treatment. pNF-H-immunoreactive neurons had overlapping size profiles and co-localisation with neurons displaying cell body immunoreactivity for parvalbumin, non-phospho-specific neurofilament medium subunit (NF-M) and non-phospho-specific neurofilament heavy subunit (NF-H), in control DRG. However, there were no significant changes in the numbers of neurons with immunoreactivity for parvalbumin (4.6%, P = 0.82), NF-M (-1%, P = 0.96) or NF-H (0%; P = 0.93) after oxaliplatin treatment, although the sizes of parvalbumin (-29%, P = 0.047), NF-M (-11%, P = 0.038) and NF-H (-28%; P = 0.0033) immunoreactive neurons were reduced. In an independent comparison of different chemotherapeutic agents, the number of pNF-H-immunoreactive neurons was significantly altered by oxaliplatin (-77.2%; P < 0.0001) and cisplatin (-35.2%; P = 0.03) but not by carboplatin or paclitaxel, and their mean cell body area was significantly changed by oxaliplatin (-31.1%; P = 0.008) but not by cisplatin, carboplatin or paclitaxel.This study has demonstrated a specific pattern of loss of pNF-H immunoreactivity in rat DRG tissue that corresponds with the relative neurotoxicity of oxaliplatin, cisplatin and carboplatin. Loss of pNF-H may be mechanistically linked to oxaliplatin-induced neuronal atrophy, and serves as a readily measureable endpoint of its neurotoxicity in the rat model.Oxaliplatin is a platinum-based chemotherapeutic agent approved for the treatment of colorectal cancer [1]. Although particularly effective for treating colorectal cancer, oxaliplatin causes neurotoxicity in a high percentage of patients [2] that is dose-limiting and can only be
Protein Aggregation and Protein Instability Govern Familial Amyotrophic Lateral Sclerosis Patient Survival  [PDF]
Qi Wang,Joshua L. Johnson,Nathalie Y.R Agar,Jeffrey N. Agar
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0060170
Abstract: The nature of the “toxic gain of function” that results from amyotrophic lateral sclerosis (ALS)-, Parkinson-, and Alzheimer-related mutations is a matter of debate. As a result no adequate model of any neurodegenerative disease etiology exists. We demonstrate that two synergistic properties, namely, increased protein aggregation propensity (increased likelihood that an unfolded protein will aggregate) and decreased protein stability (increased likelihood that a protein will unfold), are central to ALS etiology. Taken together these properties account for 69% of the variability in mutant Cu/Zn-superoxide-dismutase-linked familial ALS patient survival times. Aggregation is a concentration-dependent process, and spinal cord motor neurons have higher concentrations of Cu/Zn-superoxide dismutase than the surrounding cells. Protein aggregation therefore is expected to contribute to the selective vulnerability of motor neurons in familial ALS.
Protein Aggregation and Protein Instability Govern Familial Amyotrophic Lateral Sclerosis Patient Survival  [PDF]
Qi Wang,Joshua L Johnson,Nathalie Y.R Agar,Jeffrey N Agar
PLOS Biology , 2008, DOI: 10.1371/journal.pbio.0060170
Abstract: The nature of the “toxic gain of function” that results from amyotrophic lateral sclerosis (ALS)-, Parkinson-, and Alzheimer-related mutations is a matter of debate. As a result no adequate model of any neurodegenerative disease etiology exists. We demonstrate that two synergistic properties, namely, increased protein aggregation propensity (increased likelihood that an unfolded protein will aggregate) and decreased protein stability (increased likelihood that a protein will unfold), are central to ALS etiology. Taken together these properties account for 69% of the variability in mutant Cu/Zn-superoxide-dismutase-linked familial ALS patient survival times. Aggregation is a concentration-dependent process, and spinal cord motor neurons have higher concentrations of Cu/Zn-superoxide dismutase than the surrounding cells. Protein aggregation therefore is expected to contribute to the selective vulnerability of motor neurons in familial ALS.
Structure-Function Analysis of the Glioma Targeting NFL-TBS.40-63 Peptide Corresponding to the Tubulin-Binding Site on the Light Neurofilament Subunit  [PDF]
Raphael Berges, Julien Balzeau, Masayuki Takahashi, Chantal Prevost, Joel Eyer
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0049436
Abstract: We previously reported that a 24 amino acid peptide (NFL-TBS.40-63) corresponding to the tubulin-binding site located on the light neurofilament subunit, selectively enters in glioblastoma cells where it disrupts their microtubule network and inhibits their proliferation. Here, we analyzed the structure-function relationships using an alanine-scanning strategy, in order to identify residues essential for these biological activities. We showed that the majority of modified peptides present a decreased or total loss to penetrate in these cells, or to alter microtubules. Correspondingly, circular dichroism measurements showed that this peptide forms either β-sheet or α-helix structures according to the solvent and that alanine substitution modified or destabilized the structure, in relation with changes in the biological activities. Moreover, substitution of serine residues by phosphoserine or aspartic acid concomitantly decreased the cell penetrating activity and the structure stability. These results indicate the importance of structure for the activities, including selectivity to glioblastoma cells of this peptide, and its regulation by phosphorylation.
Sensory-motor deficits and neurofilament disorganization in gigaxonin-null mice
Thibault Ganay, Alexia Boizot, Renaud Burrer, Jean Chauvin, Pascale Bomont
Molecular Neurodegeneration , 2011, DOI: 10.1186/1750-1326-6-25
Abstract: We investigated for the first time in Gigaxonin-null mice the deterioration of the motor and sensory functions over time as well as the spatial disorganization of neurofilaments. We showed that gigaxonin depletion in mice induces mild but persistent motor deficits starting at 60 weeks of age in the 129/SvJ-genetic background, while sensory deficits were demonstrated in C57BL/6 animals. In our hands, another gigaxonin-null mouse did not display the early and severe motor deficits reported previously. No apparent neurodegeneration was observed in our knock-out mice, but dysregulation of neurofilaments in proximal and distal axons was massive. Indeed, neurofilaments were not only more abundant but they also showed the abnormal increase in diameter and misorientation that are characteristics of the human pathology.Together, our results show that gigaxonin depletion in mice induces mild motor and sensory deficits but recapitulates the severe neurofilament dysregulation seen in patients. Our model will allow investigation of the role of the gigaxonin-E3 ligase in organizing neurofilaments and may prove useful in understanding the pathological processes engaged in other neurodegenerative disorders characterized by accumulation of neurofilaments and dysfunction of the Ubiquitin Proteasome System, such as Amyotrophic Lateral Sclerosis, Huntington's, Alzheimer's and Parkinson's diseases.Giant Axonal Neuropathy (GAN) is a severe neurodegenerative disorder with early onset and a fatal outcome in young adults [1,2]. The gait instability in infancy is soon followed by a wide deterioration of the peripheral nervous system, affecting both the sensory and motor tracts. Indeed, patients experience diminution of deep tendon reflexes often leading to areflexia and a loss of the deep and superficial sensitivity. The motor deficits encompass amyotrophy, muscle weakness and evolve with skeletal deformations and loss of ambulation by the adolescence. The disease progresses with the deterio
Redox environment is an intracellular factor to operate distinct pathways for aggregation of Cu,Zn-superoxide dismutase in amyotrophic lateral sclerosis  [PDF]
Yoshiaki Furukawa
Frontiers in Cellular Neuroscience , 2013, DOI: 10.3389/fncel.2013.00240
Abstract: Dominant mutations in Cu,Zn-superoxide dismutase (SOD1) cause a familial form of amyotrophic lateral sclerosis (fALS). Misfolding and aggregation of mutant SOD1 proteins are a pathological hallmark of SOD1-related fALS cases; however, the molecular mechanism of SOD1 aggregation remains controversial. Here, I have used E. coli as a model organism and shown multiple distinct pathways of SOD1 aggregation that are dependent upon its thiol-disulfide status. Overexpression of fALS-mutant SOD1s in the cytoplasm of E. coli BL21 and SHuffleTM, where redox environment is reducing and oxidizing, respectively, resulted in the formation of insoluble aggregates with notable differences; a disulfide bond of SOD1 was completely reduced in BL21 or abnormally formed between SOD1 molecules in SHuffleTM. Depending upon intracellular redox environment, therefore, mutant SOD1 is considered to misfold/aggregate through distinct pathways, which would be relevant in description of the pathological heterogeneity of SOD1-related fALS cases.
Microglial Activation Correlates with Disease Progression and Upper Motor Neuron Clinical Symptoms in Amyotrophic Lateral Sclerosis  [PDF]
Johannes Brettschneider, Jon B. Toledo, Vivianna M. Van Deerlin, Lauren Elman, Leo McCluskey, Virginia M.-Y. Lee, John Q. Trojanowski
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039216
Abstract: Background/Aims We evaluated clinicopathological correlates of upper motor neuron (UMN) damage in amyotrophic lateral sclerosis (ALS), and analyzed if the presence of the C9ORF72 repeat expansion was associated with alterations in microglial inflammatory activity. Methods Microglial pathology was assessed by IHC with 2 different antibodies (CD68, Iba1), myelin loss by Kluver-Barrera staining and myelin basic protein (MBP) IHC, and axonal loss by neurofilament protein (TA51) IHC, performed on 59 autopsy cases of ALS including 9 cases with C9ORF72 repeat expansion. Results Microglial pathology as depicted by CD68 and Iba1 was significantly more extensive in the corticospinal tract (CST) of ALS cases with a rapid progression of disease. Cases with C9ORF72 repeat expansion showed more extensive microglial pathology in the medulla and motor cortex which persisted after adjusting for disease duration in a logistic regression model. Higher scores on the clinical UMN scale correlated with increasing microglial pathology in the cervical CST. TDP-43 pathology was more extensive in the motor cortex of cases with rapid progression of disease. Conclusions This study demonstrates that microglial pathology in the CST of ALS correlates with disease progression and is linked to severity of UMN deficits.
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