Full ablation of C9orf72 in mice causes immune system-related pathology and neoplastic events but no motor neuron defects

Sudria-Lopez, Emma; Koppers, Max; Wit, Marina de; Meer, Christiaan van der; Westeneng, Henk Jan; Zundel, Caroline A C; Youssef, Sameh A.; Harkema, Liesbeth; Bruin, Alain de; Veldink, Jan H.; Berg, Leonard H. van den; Pasterkamp, R. Jeroen

doi:10.1007/s00401-016-1581-x

Cited by 109 publications

(116 citation statements)

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“…13–16 In this study, we formally investigated autoimmune disease prevalence within C9 and FTD/MND cohorts and, consistent with our prior PGRN and svPPA study, observed elevated rates of select nonthyroid autoimmune disorders within symptomatic C9 and FTD/MND cohorts compared to NCs, typical AD, and new to this study, an FTLD-tau control group, PSP. The specific types of autoimmune diseases in the C9 and FTD/MND group cluster within the same 3 general autoimmune groups as previously described: inflammatory arthritides, cutaneous conditions, and gastrointestinal disorders.…”

Section: Discussionsupporting

confidence: 67%

“…The increased prevalence of select autoimmune diseases within FTD and ALS reported here and elsewhere 1,8 along with observations of widespread immunologic disruptions reminiscent of human autoimmune disease in PGRN 36 and C9 knockout mice 13–16 illustrate how immunodysregulation may be intrinsically linked to FTLD-TDP pathophysiology. While we show some initial results supporting a role for autoimmunity in distinguishing FTLD-TDP from FTLD-tau pathologies, direct comparisons of larger groups of high-likelihood TDP and tau cohorts are needed to determine the role of autoimmunity for its potential predictive value.…”

Section: Discussionsupporting

confidence: 59%

“…In support of this, 4 recent studies demonstrate profound disruptions of immune homeostasis exemplified by human systemic autoimmune disease in C9 knockout mice. 13–16 Specifically, lysosomal trafficking defects, cytokine elevations, widespread myeloid expansion, and T cell activation 13–15 have been observed, as well as upregulation of autoantibody production (anti-nuclear antibody, anti-cardiolipin, anti-double stranded DNA, anti-Smith, and anti-rheumatoid factor antibodies) in a manner highly evocative of human systemic lupus erythematosus. 13,15 …”

Section: Discussionmentioning

confidence: 99%

“…The observation that ablation of C9 produces immunologic but not neurologic disease suggests that these effects of C9 dysfunction may be dissociable. 13–16 We suspect that the co-occurrence of immunologic disorders within neurologic diseases reflects a shared vulnerability to each, and as such, deciphering the exact mechanisms underlying this connection will likely have near term implications for understanding, treating, and preventing autoimmune and neurodegenerative diseases alike.…”

Section: Discussionmentioning

confidence: 99%

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Increased prevalence of autoimmune disease within C9 and FTD/MND cohorts

Miller

Sturm

Camsari

et al. 2016

Neurol Neuroimmunol Neuroinflamm

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Objective:To determine the prevalence of autoimmune disease in symptomatic C9ORF72 (C9) mutation carriers and frontotemporal dementia with motor neuron disease (FTD/MND) cohorts.Methods:In this case-control study, we reviewed the clinical histories of 66 patients with FTD/MND and 57 symptomatic C9 carriers (24 overlapping cases), a total of 99 charts, for history of autoimmune disease. The prevalence of autoimmune disease in C9 and FTD/MND cohorts was determined by χ2 and Fisher exact comparisons between the combined C9 and FTD/MND group with normal control, Alzheimer disease, and progressive supranuclear palsy cohorts, as well as comparisons within C9 and FTD/MND cohorts.Results:Our combined C9 and FTD/MND cohort has a 12% prevalence of nonthyroid autoimmune disease. The prevalence of nonthyroid autoimmune disease in C9 and FTD/MND is similar to the rates in previously detailed progranulin and semantic variant primary progressive aphasia cohorts and elevated in comparison to previously collected normal control and typical Alzheimer disease cohorts, as well as a newly screened progressive supranuclear palsy cohort. Furthermore, the types of autoimmune disease in this combined C9 and FTD/MND cohort cluster within the same 3 categories previously described in progranulin and semantic variant primary progressive aphasia: inflammatory arthritides, cutaneous conditions, and gastrointestinal disorders.Conclusions:The association between selective autoimmune disease and neurodegenerative disorders unified by the underlying pathology frontotemporal lobar degeneration with TDP-43–positive inclusions (FTLD-TDP) extends to C9 and FTD/MND cohorts, providing further evidence that select autoimmune inflammation may be intrinsically linked to FTLD-TDP pathophysiology.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Increased prevalence of autoimmune disease within C9 and FTD/MND cohorts

Miller

Sturm

Camsari

et al. 2016

Neurol Neuroimmunol Neuroinflamm

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“…However, several mouse models with a general or neuron-specific deletion of C9orf72 did not develop clinical or pathological signs of motor neuron disease [2,27,28,35,42]. Instead, some models developed splenomegaly, lymphadenopathy, auto-immune disorders and neoplastic events, indicative of a primary role of the C9orf72 protein in immunity [2,35,42]. Interestingly, the C9orf72 protein has been shown to be a key player in regulation of autophagy [49].…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

et al. 2018

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The exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGG GCC repeat expansion in C9orf72 is still unclear. Two gain-of-function mechanisms are possible: repeat RNA toxicity and dipeptide repeat protein (DPR) toxicity. We here dissected both possibilities using a zebrafish model for ALS. Expression of two DPRs, glycine-arginine and proline-arginine, induced a motor axonopathy. Similarly, expanded sense and antisense repeat RNA also induced a motor axonopathy and formed mainly cytoplasmic RNA foci. However, DPRs were not detected in these conditions. Moreover, stop codon-interrupted repeat RNA still induced a motor axonopathy and a synergistic role of low levels of DPRs was excluded. Altogether, these results show that repeat RNA toxicity is independent of DPR formation. This RNA toxicity, but not the DPR toxicity, was attenuated by the RNA-binding protein Pur-alpha and the autophagy-related protein p62. Our findings demonstrate that RNA toxicity, independent of DPR toxicity, can contribute to the pathogenesis of C9orf72-associated ALS/FTD.

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Inflammation, Immunity, and amyotrophic lateral sclerosis: I. Etiology and pathology

et al. 2018

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Amyotrophic lateral sclerosis (ALS) is a severely debilitating disease characterized by progressive degeneration of motor neurons. Charcot first described ALS in 1869 ; however, its pathogenesis remains unknown, and effective treatments remain elusive. It is apparent that new paradigms must be investigated to understand the effectors of ALS, including inflammation, immune responses, and the body's response to stress and injury. Herein we discuss the potential role of the immune system in ALS pathogenesis and critically review evidence from patient and animal studies. Although immune system components may indeed play a role in ALS pathogenesis, studies implicating immune cells, antibodies, and cytokines in early disease pathology are limited. We propose more focused studies that examine the role of the immune system together with characterized pathogenesis to determine when, where, and if immune and inflammatory processes are critical to disease progression, and thus worthy targets of intervention. Muscle Nerve, 2018.

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Full ablation of C9orf72 in mice causes immune system-related pathology and neoplastic events but no motor neuron defects

Cited by 109 publications

References 4 publications

Increased prevalence of autoimmune disease within C9 and FTD/MND cohorts

Increased prevalence of autoimmune disease within C9 and FTD/MND cohorts

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

Inflammation, Immunity, and amyotrophic lateral sclerosis: I. Etiology and pathology

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