Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis

Beers, David R.; Henkel, Jenny S.; Xiao, Qin; Zhao, Weihua; Wang, Jinghong; Yen, Albert; Szabó, László; McKercher, Scott R.; Appel, Stanley H.

doi:10.1073/pnas.0607423103

Cited by 654 publications

(620 citation statements)

References 32 publications

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“…Interestingly, diminution of mSOD1 restricted to microglia leads to slower disease progression and extends survival considerably 47. In a similar manner, wild type bone marrow transfer in either lethally irradiated mSOD1 or mSOD1; PU.1 − / − mice leads to slower progression and increased survival 48, 49. These changes were suggested to be conferred by wild type microglial cells 48, 49.…”

Section: Status Of Neuroinflammation In Als and Smamentioning

confidence: 91%

“…In a similar manner, wild type bone marrow transfer in either lethally irradiated mSOD1 or mSOD1; PU.1 − / − mice leads to slower progression and increased survival 48, 49. These changes were suggested to be conferred by wild type microglial cells 48, 49. However, these reports did not take into account that donor wild type lymphoid cells, like T‐cells, may also contribute to the beneficial effect 48, 49.…”

Section: Status Of Neuroinflammation In Als and Smamentioning

confidence: 99%

“…These changes were suggested to be conferred by wild type microglial cells 48, 49. However, these reports did not take into account that donor wild type lymphoid cells, like T‐cells, may also contribute to the beneficial effect 48, 49. In vitro, mSOD1 microglia release more pro‐inflammatory cytokines like IL‐1β and TNFα, superoxide, but less neuroprotective IGF1 49, 50, 51.…”

Section: Status Of Neuroinflammation In Als and Smamentioning

confidence: 99%

“…However, these reports did not take into account that donor wild type lymphoid cells, like T‐cells, may also contribute to the beneficial effect 48, 49. In vitro, mSOD1 microglia release more pro‐inflammatory cytokines like IL‐1β and TNFα, superoxide, but less neuroprotective IGF1 49, 50, 51. Moreover, when cocultured with motor neurons, microglia could cause cell death 49, 51.…”

Section: Status Of Neuroinflammation In Als and Smamentioning

confidence: 99%

“…In vitro, mSOD1 microglia release more pro‐inflammatory cytokines like IL‐1β and TNFα, superoxide, but less neuroprotective IGF1 49, 50, 51. Moreover, when cocultured with motor neurons, microglia could cause cell death 49, 51. While much of the information points toward significant microglial contribution to disease, other reports have argued otherwise 52.…”

Section: Status Of Neuroinflammation In Als and Smamentioning

confidence: 99%

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New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

Deguise

Kothary

2017

Ann Clin Transl Neurol

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Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by motor neuron degeneration, although defects in multiple cell types and tissues have also been implicated. Three independent laboratories recently identified immune organ defects in SMA. We therefore propose a novel pathogenic mechanism contributory to SMA, resulting in higher susceptibility to infection and exacerbated disease progression caused by neuroinflammation. Overall, compromised immune function could significantly affect survival and quality of life of SMA patients. We highlight the recent findings in immune organ defects, their potential consequences on patients, our understanding of neuroinflammation in SMA, and new research hypotheses in SMA pathogenesis.

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Section: Status Of Neuroinflammation In Als and Smamentioning

confidence: 91%

Section: Status Of Neuroinflammation In Als and Smamentioning

confidence: 99%

Section: Status Of Neuroinflammation In Als and Smamentioning

confidence: 99%

Section: Status Of Neuroinflammation In Als and Smamentioning

confidence: 99%

Section: Status Of Neuroinflammation In Als and Smamentioning

confidence: 99%

See 3 more Smart Citations

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

Deguise

Kothary

2017

Ann Clin Transl Neurol

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Characterization of Gene Expression Phenotype in Amyotrophic Lateral Sclerosis Monocytes

et al. 2017

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IMPORTANCE Amyotrophic lateral sclerosis (ALS) is a common adult-onset neurodegenerative disease characterized by selective loss of upper and lower motor neurons. Patients with ALS have persistent peripheral and central inflammatory responses including abnormally functioning T cells and activated microglia. However, much less is known about the inflammatory gene profile of circulating innate immune monocytes in these patients.OBJECTIVE To characterize the transcriptomics of peripheral monocytes in patients with ALS. DESIGN, SETTING, AND PARTICIPANTS Monocytes were isolated from peripheral blood of 43 patients with ALS and 22 healthy control individuals. Total RNA was extracted from the monocytes and subjected to deep RNA sequencing, and these results were validated by quantitative reverse transcription polymerase chain reaction. MAIN OUTCOMES AND MEASURESThe differential expressed gene signatures of these monocytes were identified using unbiased RNA sequencing strategy for gene expression profiling. RESULTSThe demographics between the patients with ALS (mean [SD] age, 58.8 [1.57] years; 55.8% were men and 44.2% were women; 90.7% were white, 4.65% were Hispanic, 2.33% were black, and 2.33% were Asian) and control individuals were similar (mean [SD] age, 57.6 [2.15] years; 50.0% were men and 50.0% were women; 90.9% were white, none were Hispanic, none were black, and 9.09% were Asian). RNA sequencing data from negative selected monocytes revealed 233 differential expressed genes in ALS monocytes compared with healthy control monocytes. Notably, ALS monocytes demonstrated a unique inflammation-related gene expression profile, the most prominent of which, including IL1B, IL8, FOSB, CXCL1, and CXCL2, were confirmed by quantitative reverse transcription polymerase chain reaction (IL8, mean [SE], 1.

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Rodent Models of Amyotrophic Lateral Sclerosis

2015

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Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease affecting upper and lower motor neurons in the CNS. Patients with ALS develop extensive muscle wasting and atrophy leading to paralysis and death 3-5 years after disease onset. ALS may be familial (fALS 10%) or sporadic ALS (sALS, 90%). The large majority of fALS) cases are due to genetic mutations in the Superoxide dismutase 1 gene (SOD1, 15% of fALS) and repeat nucleotide expansions in the gene encoding C9ORF72 (around 40-50% of fALS and ~10% of sALS). From a wide range of pathological studies the general conclusion is that ALS disease is mediated through aberrant protein homeostasis (ie ER stress and autophagy) and/or changes in RNA processing (as seen in all non-SOD1-mediated ALS). In all of these cases, animal models suggest that the disease is mediated non-cell-autonomously, i.e. not only motor neurons are involved, but glial cells including microglia, astrocytes and oligodendrocytes and other neuronal subpopulations are also implicated in disease pathogenesis. This overview will give a chronological overview of a wide range of different ALS rodent models generated so far with a thorough description of their intrinsic advantages and disadvantages. We will focus on their respective correlation with disease as seen in humans and their potential for understanding basic disease biology. As RNA processing has more recently come to the foreground of ALS research, we will mainly focus on a thorough description of the most recently generated ALS rodent models.

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Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis

Cited by 654 publications

References 32 publications

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

Characterization of Gene Expression Phenotype in Amyotrophic Lateral Sclerosis Monocytes

Rodent Models of Amyotrophic Lateral Sclerosis

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