A role for neurofilaments in the pathogenesis of amyotrophic lateral sclerosis

1995 ◽  
Vol 73 (9-10) ◽  
pp. 593-597 ◽  
Author(s):  
Jean-Pierre Julien
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Axonal Transport ◽  
Motor Neurons ◽  
Intracellular Transport ◽  
Late Onset ◽  
Cytoskeletal Proteins ◽  
H Gene ◽  
Abnormal Accumulation ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a late-onset degenerative disease of motor neurons, characterized by abnormal accumulation of neurofilaments (NFs) in perikarya and proximal axons. Two lines of evidence suggest that neurofilament accumulation can play a crucial role in ALS pathogenesis. First, transgenic mouse models overexpressing NF proteins were found to develop motor neuron degeneration and, second, variant alleles of the NF heavy-subunit (NF-H) gene have been found in some human ALS patients. Our axonal transport studies with transgenic mice overexpressing the human NF-H gene, a model of ALS, revealed defects of intracellular transport not only for neurofilament proteins but also for other cytoskeletal proteins and organelles such as mitochondria. Therefore, we propose that neurofilament accumulation in mice causes neurodegeneration by disrupting axonal transport, a mechanism that may account for the pathogenesis of ALS.Key words: amyotrophic lateral sclerosis, neurofilaments, transgenic mice, axonal transport.

scholarly journals New perspectives on cytoskeletal dysregulation and mitochondrial mislocalization in amyotrophic lateral sclerosis

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Frances Theunissen ◽  
Phillip K. West ◽  
Samuel Brennan ◽  
Bojan Petrović ◽  
Kosar Hooshmand ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Retrograde Transport ◽  
Cytoskeletal Proteins ◽  
Charcot Marie Tooth Disease ◽  
Mitochondrial Homeostasis ◽  
Axonal Projections ◽  
Cytoskeletal Network ◽  
Brain And Spinal Cord ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective, early degeneration of motor neurons in the brain and spinal cord. Motor neurons have long axonal projections, which rely on the integrity of neuronal cytoskeleton and mitochondria to regulate energy requirements for maintaining axonal stability, anterograde and retrograde transport, and signaling between neurons. The formation of protein aggregates which contain cytoskeletal proteins, and mitochondrial dysfunction both have devastating effects on the function of neurons and are shared pathological features across several neurodegenerative conditions, including ALS, Alzheimer's disease, Parkinson's disease, Huntington’s disease and Charcot-Marie-Tooth disease. Furthermore, it is becoming increasingly clear that cytoskeletal integrity and mitochondrial function are intricately linked. Therefore, dysregulations of the cytoskeletal network and mitochondrial homeostasis and localization, may be common pathways in the initial steps of neurodegeneration. Here we review and discuss known contributors, including variants in genetic loci and aberrant protein activities, which modify cytoskeletal integrity, axonal transport and mitochondrial localization in ALS and have overlapping features with other neurodegenerative diseases. Additionally, we explore some emerging pathways that may contribute to this disruption in ALS.

scholarly journals Early upregulation of cytosolic phospholipase A2α in motor neurons is induced by misfolded SOD1 in a mouse model of amyotrophic lateral sclerosis

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Yafa Fetfet Malada Edelstein ◽  
Yulia Solomonov ◽  
Nurit Hadad ◽  
Leenor Alfahel ◽  
Adrian Israelson ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Motor Neurons ◽  
Dependent Manner ◽  
Mutant Sod1 ◽  
Over Expression ◽  
Cytosolic Phospholipase ◽  
Misfolded Sod1 ◽  
Lateral Sclerosis

Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal multifactorial neurodegenerative disease characterized by the selective death of motor neurons. Cytosolic phospholipase A2 alpha (cPLA2α) upregulation and activation in the spinal cord of ALS patients has been reported. We have previously shown that cPLA2α upregulation in the spinal cord of mutant SOD1 transgenic mice (SOD1G93A) was detected long before the development of the disease, and inhibition of cPLA2α upregulation delayed the disease’s onset. The aim of the present study was to determine the mechanism for cPLA2α upregulation. Methods Immunofluorescence analysis and western blot analysis of misfolded SOD1, cPLA2α and inflammatory markers were performed in the spinal cord sections of SOD1G93A transgenic mice and in primary motor neurons. Over expression of mutant SOD1 was performed by induction or transfection in primary motor neurons and in differentiated NSC34 motor neuron like cells. Results Misfolded SOD1 was detected in the spinal cord of 3 weeks old mutant SOD1G93A mice before cPLA2α upregulation. Elevated expression of both misfolded SOD1 and cPLA2α was specifically detected in the motor neurons at 6 weeks with a high correlation between them. Elevated TNFα levels were detected in the spinal cord lysates of 6 weeks old mutant SOD1G93A mice. Elevated TNFα was specifically detected in the motor neurons and its expression was highly correlated with cPLA2α expression at 6 weeks. Induction of mutant SOD1 in primary motor neurons induced cPLA2α and TNFα upregulation. Over expression of mutant SOD1 in NSC34 cells caused cPLA2α upregulation which was prevented by antibodies against TNFα. The addition of TNFα to NSC34 cells caused cPLA2α upregulation in a dose dependent manner. Conclusions Motor neurons expressing elevated cPLA2α and TNFα are in an inflammatory state as early as at 6 weeks old mutant SOD1G93A mice long before the development of the disease. Accumulated misfolded SOD1 in the motor neurons induced cPLA2α upregulation via induction of TNFα.

scholarly journals Neurofilaments and Orthograde Transport Are Reduced in Ventral Root Axons of Transgenic Mice that Express Human SOD1 with a G93A Mutation

1997 ◽  
Vol 139 (5) ◽  
pp. 1307-1315 ◽  
Author(s):  
Bin Zhang ◽  
Pang-hsien Tu ◽  
Farhad Abtahian ◽  
John Q. Trojanowski ◽  
Virginia M.-Y. Lee
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Axonal Transport ◽  
Motor Neurons ◽  
Temporal Correlation ◽  
Motor Weakness ◽  
Concomitant Reduction ◽  
Ventral Roots ◽  
Human Sod1 ◽  
Lateral Sclerosis

Mice engineered to express a transgene encoding a human Cu/Zn superoxide dismutase (SOD1) with a Gly93 → Ala (G93A) mutation found in patients who succumb to familial amyotrophic lateral sclerosis (FALS) develop a rapidly progressive and fatal motor neuron disease (MND) similar to amyotrophic lateral sclerosis (ALS). Hallmark ALS lesions such as fragmentation of the Golgi apparatus and neurofilament (NF)-rich inclusions in surviving spinal cord motor neurons as well as the selective degeneration of this population of neurons were also observed in these animals. Since the mechanism whereby mutations in SOD1 lead to MND remains enigmatic, we asked whether NF inclusions in motor neurons compromise axonal transport during the onset and progression of MND in a line of mice that contained ∼30% fewer copies of the transgene than the original G93A (Gurney et al., 1994). The onset of MND was delayed in these mice compared to the original G93A mice, but they developed the same neuropathologic abnormalities seen in the original G93A mice, albeit at a later time point with fewer vacuoles and more NF inclusions. Quantitative Western blot analyses showed a progressive decrease in the level of NF proteins in the L5 ventral roots of G93A mice and a concomitant reduction in axon caliber with the onset of motor weakness. By ∼200 d, both fast and slow axonal transports were impaired in the ventral roots of these mice coincidental with the appearance of NF inclusions and vacuoles in the axons and perikarya of vulnerable motor neurons. This is the first demonstration of impaired axonal transport in a mouse model of ALS, and we infer that similar impairments occur in authentic ALS. Based on the temporal correlation of these impairments with the onset of motor weakness and the appearance of NF inclusions and vacuoles in vulnerable motor neurons, the latter lesions may be the proximal cause of motor neuron dysfunction and degeneration in the G93A mice and in FALS patients with SOD1 mutations.

Otolaryngologist’s role in the diagnosis of amyotrophic lateral sclerosis

2021 ◽  
Vol 14 (2) ◽  
pp. e234504
Author(s):  
Joana Borges Costa ◽  
Diogo Pereira ◽  
Delfim Duarte ◽  
Miguel Viana
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Clinical Presentation ◽  
Late Onset ◽  
History Of ◽  
Dysarthric Speech ◽  
Selective Death ◽  
Hypernasal Voice ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and late-onset fatal neurodegenerative disease characterised by selective death of motor neurons. The aetiology of ALS is still unknown and it is extremely heterogeneous in genetics and clinical presentation, being the respiratory failure the usual cause of death. We describe a case of a 61-year-old male patient referred to the otolaryngology consultation for a 6-month history of progressive solid dysphagia and dysphonia. The patient presented several voice alterations such as a dysarthric speech with hypernasal voice which evoked the hypothesis of a neuromuscular disease. That patient was observed by a neurologist and was submitted to an electromyography that confirmed the ALS diagnosis. This case highlights the key role of otolaryngologists in the diagnosis of ALS, in a way that many patients with a bulbar ALS form are initially studied by an otolaryngologist.

scholarly journals Bidens pilosa Extract Administered after Symptom Onset Attenuates Glial Activation, Improves Motor Performance, and Prolongs Survival in a Mouse Model of Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Yasuhiro Kosuge ◽  
Erina Kaneko ◽  
Hiroshi Nango ◽  
Hiroko Miyagishi ◽  
Kumiko Ishige ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Mouse Model ◽  
Motor Neurons ◽  
Motor Performance ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Bidens Pilosa ◽  
Neuronal Marker ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder characterized by progressive paralysis resulting from the death of upper and lower motor neurons. There is currently no effective pharmacological treatment for ALS, and the two approved drugs riluzole and edaravone have limited effects on the symptoms and only slightly prolong the life of patients. Therefore, the development of effective therapeutic strategies is of paramount importance. In this study, we investigated whether Miyako Island Bidens pilosa (MBP) can alleviate the neurological deterioration observed in a superoxide dismutase-1 G93A mutant transgenic mouse (G93A mouse) model of ALS. We orally administered 2 g/kg/day of MBP to G93A mice at the onset of symptoms of neurodegeneration (15 weeks old) until death. Treatment with MBP markedly prolonged the life of ALS model mice by approximately 20 days compared to that of vehicle-treated ALS model mice and significantly improved motor performance. MBP treatment prevented the reduction in SMI32 expression, a neuronal marker protein, and attenuated astrocyte (detected by GFAP) and microglia (detected by Iba-1) activation in the spinal cord of G93A mice at the end stage of the disease (18 weeks old). Our results indicate that MBP administered after the onset of ALS symptoms suppressed the inflammatory activation of microglia and astrocytes in the spinal cord of the G93A ALS model mice, thus improving their quality of life. MBP may be a potential therapeutic agent for ALS.

Activation of the stress-activated MAP kinase, p38, but not JNK in cortical motor neurons during early presymptomatic stages of amyotrophic lateral sclerosis in transgenic mice

2005 ◽  
Vol 1045 (1-2) ◽  
pp. 185-198 ◽  
Author(s):  
Silvina S. Holasek ◽  
Thomas M. Wengenack ◽  
Karunya K. Kandimalla ◽  
Carolina Montano ◽  
Dawn M. Gregor ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Map Kinase ◽  
Motor Neurons ◽  
Cortical Motor ◽  
Lateral Sclerosis

scholarly journals BiP Heterozigosity Aggravates Pathological Deterioration in Experimental Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 22 (22) ◽  
pp. 12533
Author(s):  
Marta Gómez-Almería ◽  
Sonia Burgaz ◽  
Carlos Costas-Insua ◽  
Carmen Rodríguez-Cueto ◽  
Irene Santos-García ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Motor Neurons ◽  
Cb1 Receptor ◽  
Mutant Mice ◽  
Nissl Staining ◽  
Neuroprotective Effects ◽  
Neurological Score ◽  
6 Hydroxydopamine ◽  
Lateral Sclerosis

In the present study, we investigated the involvement of the chaperone protein BiP (also known as GRP78 or Hspa5), a master regulator of intracellular proteostasis, in two mouse models of neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). To this end, we used mice bearing partial genetic deletion of the BiP gene (BiP+/− mice), which, for the ALS model, were crossed with mutant SOD1 (mSOD1) transgenic mice to generate mSOD1/BiP+/− double mutant mice. Our data revealed a more intense neurological decline in the double mutants, reflected in a greater deterioration of the neurological score and rotarod performance, with also a reduced animal survival, compared to mSOD1 transgenic mice. Such worsening was associated with higher microglial (labelled with Iba-1 immunostaining) and, to a lesser extent, astroglial (labelled with GFAP immunostaining) immunoreactivities found in the double mutants, but not with a higher loss of spinal motor neurons (labelled with Nissl staining) in the spinal cord. The morphological analysis of Iba-1 and GFAP-positive cells revealed a higher presence of activated cells, characterized by elevated cell body size and shorter processes, in double mutants compared to mSOD1 mice with normal BiP expression. In the case of the PD model, BiP+/− mice were unilaterally lesioned with the parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). In this case, however, we did not detect a greater susceptibility to damage in mutant mice, as the motor defects caused by 6-OHDA in the pole test and the cylinder rearing test, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity (labelled with CD68 and GFAP immunostaining) detected in the substantia nigra were of similar magnitude in BiP+/− mice compared with wildtype animals. Therefore, our findings support the view that a dysregulation of the protein BiP may contribute to ALS pathogenesis. As BiP has been recently related to cannabinoid type-1 (CB1) receptor function, our work also opens the door to future studies on a possible link between BiP and the neuroprotective effects of cannabinoids that have been widely reported in this neuropathological context. In support of this possibility, preliminary data indicate that CB1 receptor levels are significantly reduced in mSOD1 mice having partial deletion of BiP gene.

scholarly journals Homozygous SOD1 Variation L144S Produces a Severe Form of Amyotrophic Lateral Sclerosis in an Iranian Family

2021 ◽  
Vol 8 (1) ◽  
pp. e645
Author(s):  
Delia Gagliardi ◽  
Minoo Ahmadinejad ◽  
Roberto Del Bo ◽  
Megi Meneri ◽  
Giacomo Pietro Comi ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Early Onset ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Muscular Atrophy ◽  
Severe Form ◽  
Iranian Family ◽  
Fast Progression ◽  
Lateral Sclerosis

ObjectivesAmyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by degeneration of motor neurons determining progressive muscular atrophy, weakness, and death from respiratory failure.MethodsHere, we report clinical and molecular findings of a novel Iranian family affected with a severe form of early-onset familial ALS.ResultsThree siblings born to consanguineous parents developed a form of ALS characterized by early-onset lower limb involvement and a fast progression, proving fatal at age 16 years for 1 of them. Molecular analysis of the SOD1 gene revealed the homozygous substitution c.434T>C in exon 5 resulting in the amino acid change p.Leu144Ser (L144S), previously reported as a dominant variant. Both parents were heterozygous carriers. The probands' mother recently developed a late-onset ALS with predominant upper motor neuron involvement.DiscussionThis report adds p.L144S to the short list of homozygous SOD1 variants and suggests that the development of an earlier-onset and/or faster disease progression can occur when 2 mutated alleles are present.

Sertoli cells improve survival of motor neurons in SOD1 transgenic mice, a model of amyotrophic lateral sclerosis

2005 ◽  
Vol 196 (2) ◽  
pp. 235-243 ◽  
Author(s):  
Richelle Hemendinger ◽  
Jay Wang ◽  
Saafan Malik ◽  
Rafal Persinski ◽  
Jane Copeland ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Motor Neurons ◽  
Sertoli Cells ◽  
Survival Of Motor Neurons ◽  
Lateral Sclerosis

scholarly journals A neurotoxic peripherin splice variant in a mouse model of ALS

2003 ◽  
Vol 160 (6) ◽  
pp. 939-949 ◽  
Author(s):  
Janice Robertson ◽  
Mohammad M. Doroudchi ◽  
Minh Dang Nguyen ◽  
Heather D. Durham ◽  
Michael J. Strong ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Motor Neurons ◽  
Splice Variants ◽  
Superoxide Dismutase 1 ◽  
Specific Antibodies ◽  
Axonal Spheroids ◽  
Familial Als ◽  
Nif Proteins ◽  
Lateral Sclerosis

Peripherin, a neuronal intermediate filament (nIF) protein found associated with pathological aggregates in motor neurons of patients with amyotrophic lateral sclerosis (ALS) and of transgenic mice overexpressing mutant superoxide dismutase-1 (SOD1G37R), induces the selective degeneration of motor neurons when overexpressed in transgenic mice. Mouse peripherin is unique compared with other nIF proteins in that three peripherin isoforms are generated by alternative splicing. Here, the properties of the peripherin splice variants Per 58, Per 56, and Per 61 have been investigated in transfected cell lines, in primary motor neurons, and in transgenic mice overexpressing peripherin or overexpressing SOD1G37R. Of the three isoforms, Per 61 proved to be distinctly neurotoxic, being assembly incompetent and inducing degeneration of motor neurons in culture. Using isoform-specific antibodies, Per 61 expression was detected in motor neurons of SOD1G37R transgenic mice but not of control or peripherin transgenic mice. The Per 61 antibody also selectively labeled motor neurons and axonal spheroids in two cases of familial ALS and immunoprecipitated a higher molecular mass peripherin species from disease tissue. This evidence suggests that expression of neurotoxic splice variants of peripherin may contribute to the neurodegenerative mechanism in ALS.

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