Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice

Yamanaka, Koji; Boillée, Séverine; Roberts, Elizabeth A.; Garcia, Michael L.; McAlonis-Downes, Melissa; Mikse, Oliver R.; Cleveland, Don W.; Goldstein, Lawrence S.B.

doi:10.1073/pnas.0802556105

Cited by 264 publications

(191 citation statements)

References 29 publications

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“…Recent in vitro and in vivo models convincingly demonstrated that astrocytes mediate, at least in part, disease progression in SOD1 fALS models (1,8,9,31,32). This finding, in turn, led to the concept of non-cell-autonomous neurodegeneration.…”

Section: Discussionmentioning

confidence: 94%

“…We next sought to determine whether mutant M337V astrocytes exert a non-cell-autonomous toxic effect on MNs, similar to that described for mutant SOD1 rodent astrocytes (1,8,9,31,32). To this end, we first verified the utility of survival analysis by longitudinal microscopy for detecting non-cell-autonomous toxic effects of glia on WT MNs derived from human iPSCs by coculturing HB9:GFP-transfected WT MNs on murine primary astroglia overexpressing either hSOD1 WT or hSOD1 G93A .…”

Section: Resultsmentioning

confidence: 99%

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Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy

Serio

Bilican

Barmada

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

316

331

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Glial proliferation and activation are associated with disease progression in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia. In this study, we describe a unique platform to address the question of cell autonomy in transactive response DNAbinding protein (TDP-43) proteinopathies. We generated functional astroglia from human induced pluripotent stem cells carrying an ALScausing TDP-43 mutation and show that mutant astrocytes exhibit increased levels of TDP-43, subcellular mislocalization of TDP-43, and decreased cell survival. We then performed coculture experiments to evaluate the effects of M337V astrocytes on the survival of wild-type and M337V TDP-43 motor neurons, showing that mutant TDP-43 astrocytes do not adversely affect survival of cocultured neurons. These observations reveal a significant and previously unrecognized glial cell-autonomous pathological phenotype associated with a pathogenic mutation in TDP-43 and show that TDP-43 proteinopathies do not display an astrocyte non-cell-autonomous component in cell culture, as previously described for SOD1 ALS. This study highlights the utility of induced pluripotent stem cell-based in vitro disease models to investigate mechanisms of disease in ALS and other TDP-43 proteinopathies.glia | motor neuron disease | disease modeling T ransactive response DNA-binding protein (TDP-43) is the major component of ubiquitinated cytoplasmic and nuclear inclusions in neurons and astroglia in amyotrophic lateral sclerosis (ALS) and a subgroup of frontotemporal lobar degeneration (FTLD-TDP) (1-3). These pathological hallmarks provide a unifying description of a range of conditions defined as TDP-43 proteinopathies (4). At present, >30 mutations in the TDP-43 gene (TARDBP) have been linked to familial ALS (fALS) (5), strongly suggesting a causative role for TDP-43 in the pathogenesis of ALS.Accumulating evidence from experimental systems implicating non-cell-autonomous mechanisms in ALS has highlighted the importance of the glial cellular environment to motor neuron (MN) degeneration (1,3,(6)(7)(8)(9). In vivo rodent models of ALS with lineage-specific SOD1 expression have particularly influenced our understanding of the nonneuronal contribution to disease progression. Glial expression of mutant SOD1 cannot initiate MN disease on its own, but is necessary for disease progression (6, 7). Furthermore, astrogliosis precedes MN degeneration in some animal models and is a dominant feature of all human ALS pathology (4, 6, 10). Collectively, these observations highlight the need to better understand the nature of astroglial pathology in ALS. Combining developmental neurobiological principles of cell fate determination with human induced pluripotent stem cell (iPSC) lines derived from patients carrying ALS disease-causing mutations may provide important insights into astroglia pathology.We recently generated human MNs from iPSC lines derived from a fALS patient and demonstrated that the M337V TDP-43 mutation confers cell-autonomous toxicity to MNs (11). More...

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Section: Discussionmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy

Serio

Bilican

Barmada

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

316

331

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“…It has been extensively reported that glial cells contribute to MN degeneration, both in animal models [33][34][35] and in ALS patients [36]. Thus, we analyzed both The results showed that PRE-084 administration significantly reduced microglial, but not astroglial immunoreactivity in the ventral horn of SOD1 animals (Figs.…”

Section: Pre-084 Administration Reduces Microglial But Not Astroglialmentioning

confidence: 97%

Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice

et al. 2012

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Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by progressive weakness, muscle atrophy, and paralysis due to the loss of upper and lower motoneurons (MNs). Sigma-1 receptor (sigma-1R) activation promotes neuroprotection after ischemic and traumatic injuries to the central nervous system. We recently reported that sigma-1R agonist (PRE-084) improves the survival of MNs after root avulsion injury in rats. Moreover, a mutation of the sigma-1R leading to frontotemporal lobar degeneration/amyotrophic lateral sclerosis (ALS) was recently described in human patients. In the present study, we analyzed the potential therapeutic effect of the sigma-1R agonist (PRE-084) in the SOD1 G93A mouse model of ALS. Mice were daily administered with PRE-084 (0.25 mg/kg) from 8 to 16 weeks of age. Functional outcome was assessed by electrophysiological tests and computerized analysis of locomotion. Histological, immunohistochemical analyses and Western blot of the spinal cord were performed. PRE-084 administration from 8 weeks of age improved the function of MNs, which was manifested by maintenance of the amplitude of muscle action potentials and locomotor behavior, and preserved neuromuscular connections and MNs in the spinal cord. Moreover, it extended survival in both female and male mice by more than 15 %. Delayed administration of PRE-084 from 12 weeks of age also significantly improved functional outcome and preservation of the MNs. There was an induction of protein kinase C-specific phosphorylation of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor in SOD1 G93A animals, and a reduction of the microglial reactivity compared with untreated mice. PRE-084 exerts a dual therapeutic contribution, modulating NMDA Ca 2+ influx to protect MNs, and the microglial reactivity to ameliorate the MN environment. In conclusion, sigma-1R agonists, such as PRE-084, may be promising candidates for a therapeutical strategy of ALS.

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“…Resveratrol Administration Reduces Microglial Immunoreactivity in the SOD1 G93A Mice Spinal Cord It has been extensively reported that glial cells contribute to MN degeneration both in ALS patients [39] and animal models [40][41][42]. We evaluated astroglial (GFAP labeled cells) and microglial (Iba-1 labeled cells) immunoreactivity in the anterior horns of lumbar spinal cord sections in order to assess whether resveratrol treatment influenced the response of glial cells.…”

Section: Resveratrol Administration Reduces Spinal Motoneuron Degenermentioning

confidence: 99%

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

et al. 2014

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Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease that causes progressive paralysis and death due to degeneration of motoneurons in spinal cord, brainstem and motor cortex. Nowadays, there is no effective therapy and patients die 2-5 years after diagnosis. Resveratrol (trans-3,4′,5-trihydroxystilbene) is a natural polyphenol found in grapes, with promising neuroprotective effects since it induces expression and activation of several neuroprotective pathways involving Sirtuin1 and AMPK. The objective of this work was to assess the effect of resveratrol administration on SOD1 G93A ALS mice. We determined the onset of symptoms by rotarod test and evaluated upper and lower motoneuron function using electrophysiological tests.We assessed the survival of the animals and determined the number of spinal motoneurons. Finally, we further investigated resveratrol mechanism of action by means of western blot and immunohistochemical analysis. Resveratrol treatment from 8 weeks of age significantly delayed disease onset and preserved lower and upper motoneuron function in female and male animals. Moreover, resveratrol significantly extended SOD1 G93A mice lifespan and promoted survival of spinal motoneurons. Delayed resveratrol administration from 12 weeks of age also improved spinal motoneuron function preservation and survival. Further experiments revealed that resveratrol protective effects were associated with increased expression and activation of Sirtuin 1 and AMPK in the ventral spinal cord. Both mediators promoted normalization of the autophagic flux and, more importantly, increased mitochondrial biogenesis in the SOD1 G93A spinal cord. Taken together, our findings suggest that resveratrol may represent a promising therapy for ALS.

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Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice

Cited by 264 publications

References 29 publications

Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy

Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy

Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

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