<i>C9orf72</i> and <i>smcr8</i> mutant mice reveal MTORC1 activation due to impaired lysosomal degradation and exocytosis

Shao, Qiang; Yang, Mei; Chen, Liang; Ma, Li; Zhang, Wei; Jiang, Zhiwen; Luo, Jun; Lee, Jae‐Kyung; Liang, Chengyu; Chen, Jianfu

doi:10.1080/15548627.2019.1703353

Cited by 43 publications

(54 citation statements)

References 56 publications

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“…The C9orf72/SMCR8/WDR41 complex associates with the ATG8 autophagy receptor network and influences activity of the ULK1-RB1CC1-ATG13-ATG101 autophagy initiation complex (RB1CC1 was detected in both our SMCR8 and C9orf72 protein interactomes, Tables S1, S2) [22,28,29,31,34]. C9orf72 and SMCR8 reportedly also play roles in regulating mTORC1 and TFEB autophagy and lysosomal gene transcription factors upstream of autophagy [26,31,32,34,57,103,109,110]. Ugolino et al [32], however, indicated a negative effect of C9orf72 on autophagy, and Yang et al [31] reported increased autophagic flux in C9orf72 knockdown MEF cells, opposite to the reduction they saw in SMCR8-deficient cells.…”

Section: Discussionmentioning

confidence: 87%

“…However, subsequent studies detected no or only mild motor function defects in mice deficient for murine C9orf72 ortholog 3110043O21Rik [45]. On the other hand, in a gain-offunction C9ALS/FTD mouse model, Shao et al [57] found that 3110043O21Rik haploinsufficiency or loss was associated with increased motor behavior deficits in a dose-dependent manner, while Liang et al [25] reported that Smcr8 knockout (KO) mice displayed motor behavior defects and axonal swelling. While effects on motor function are uncertain, immune system pathology, spleen and lymph node enlargement, defects in macrophage, myeloid and microglial cell function, altered lysosomal trafficking, and decreased body weight and survival have all been reported for C9orf72 or SMCR8 knockout mice [21,28,32,45,[58][59][60][61][62][63][64][65].…”

Section: Introductionmentioning

confidence: 99%

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C9orf72-associated SMCR8 protein binds in the ubiquitin pathway and with proteins linked with neurological disease

Goodier

Soares

Pereira

et al. 2020

acta neuropathol commun

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A pathogenic GGGCCC hexanucleotide expansion in the first intron/promoter region of the C9orf72 gene is the most common mutation associated with amyotrophic lateral sclerosis (ALS). The C9orf72 gene product forms a complex with SMCR8 (Smith-Magenis Syndrome Chromosome Region, Candidate 8) and WDR41 (WD Repeat domain 41) proteins. Recent studies have indicated roles for the complex in autophagy regulation, vesicle trafficking, and immune response in transgenic mice, however a direct connection with ALS etiology remains unclear. With the aim of increasing understanding of the multi-functional C9orf72-SMCR8-WDR41 complex, we determined by mass spectrometry analysis the proteins that directly associate with SMCR8. SMCR8 protein binds many components of the ubiquitin-proteasome system, and we demonstrate its poly-ubiquitination without obvious degradation. Evidence is also presented for localization of endogenous SMCR8 protein to cytoplasmic stress granules. However, in several cell lines we failed to reproduce previous observations that C9orf72 protein enters these granules. SMCR8 protein associates with many products of genes associated with various Mendelian neurological disorders in addition to ALS, implicating SMCR8-containing complexes in a range of neuropathologies. We reinforce previous observations that SMCR8 and C9orf72 protein levels are positively linked, and now show in vivo that SMCR8 protein levels are greatly reduced in brain tissues of C9orf72 gene expansion carrier individuals. While further study is required, these data suggest that SMCR8 protein level might prove a useful biomarker for the C9orf72 expansion in ALS.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

C9orf72-associated SMCR8 protein binds in the ubiquitin pathway and with proteins linked with neurological disease

Goodier

Soares

Pereira

et al. 2020

acta neuropathol commun

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“…Likewise, when the number of early endosomes, late endosomes and lysosomes where counted in C9orf72 ALS/FTD iMNs and compared to control iMNs, the loss of lysosomes was the major difference observed between the groups supporting the idea of a potential disruption in the endosomallysosomal pathways and consequently, a contribution to neurodegeneration(107,108). These findings are reinforced by studies reporting enlarged lysosomes in C9orf72 postmortem patient tissues and previous studies proposing that the function of the C9orf72 protein is linked to the regulation of lysosomes and autophagy(30,(130)(131)(132)(133). Our data suggests that similar dysfunctions are present in C9orf72 microglia as shown in our in vitro culture model, but also inC9orf72 ALS/FTD patient postmortem brain tissues.…”

mentioning

confidence: 60%

Cellular and molecular phenotypes ofC9orf72ALS/FTD patient derived iPSC-microglia mono-cultures

Lorenzini

Alsop

Levy

et al. 2020

Preprint

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Background: A mutation in the C9orf72 gene is the most common genetic mutation of familial and sporadic ALS, as well as familial FTD. While prior studies have focused on elucidating the mechanisms of neuronal dysfunction and neurodegeneration associated with this genetic mutation, the contribution of microglia to disease pathogenesis in the ALS/FTD disease spectrum remains poorly understood. Methods: Here, we generated a new disease model consisting of cultured C9orf72 ALS/FTD patient-derived induced pluripotent stem cells differentiated into microglia (iPSC-MG). We used this model to study the intrinsic cellular and molecular phenotypes of microglia triggered by the C9orf72 gene mutation. Results: We show that C9orf72 ALS/FTD iPSC-MG have a similar transcriptional profile compared to control iPSC-MG, despite the presence of C9orf72-associated phenotypes including reduced C9orf72 protein levels and dipeptide-repeat protein translation. Interestingly, C9orf72 ALS/FTD iPSC-MG exhibit intrinsic dysfunction of phagocytic activity upon exposure to Aβ or brain synaptoneurosomes and display a heightened inflammatory response. Detailed analysis of the endosomal and lysosomal pathways revealed altered expression of endosomal marker early endosome antigen 1 and lysosomal associated membrane protein 1 in C9orf72 ALS/FTD iPSC-MG, which was confirmed in patient postmortem tissues. Conclusions: These findings demonstrate that unstimulated C9orf72 iPSC-MG mono-cultures share a largely similar transcriptome profile with control microglia, despite the presence of C9orf72 disease phenotypes. The dysfunction of the endosomal-lysosomal pathway as demonstrated by aberrant microglia phagocytosis and engulfment of cellular debris and brain pathogens suggests that disease-related microglia phenotypes are not intrinsic but instead require microglia to be activated. In summary, the C9orf72 iPSC-MG culture system provides a novel human disease model to study the role of microglia in C9orf72 ALS/FTD disease pathogenesis.

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“…C9orf72-deficient mice exhibit autophagy defects in the spleen and liver, which are accompanied by increased lysosomal proteins and increased autophagy initiation (Table 4 ) [ 87 , 107 ]. Mice deficient in SMCR8, a factor in the tripartite complex with C9orf72, display similar autophagy defects as well as inflammatory and autoimmune phenotypes (Table 4 ) [ 64 , 79 , 103 , 127 ]. Moreover, a combined knockout of C9orf72 and SMCR8 induces even more severe immune disturbances (Table 4 ) [ 103 ].…”

Section: Assessment Of the Loss-of-function Mechanism In C9mentioning

confidence: 99%

C9orf72 loss-of-function: a trivial, stand-alone or additive mechanism in C9 ALS/FTD?

2020

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A repeat expansion in C9orf72 is responsible for the characteristic neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in a still unresolved manner. Proposed mechanisms involve gain-of-functions, comprising RNA and protein toxicity, and loss-of-function of the C9orf72 gene. Their exact contribution is still inconclusive and reports regarding loss-of-function are rather inconsistent. Here, we review the function of the C9orf72 protein and its relevance in disease. We explore the potential link between reduced C9orf72 levels and disease phenotypes in postmortem, in vitro, and in vivo models. Moreover, the significance of loss-of-function in other non-coding repeat expansion diseases is used to clarify its contribution in C9orf72 ALS/FTD. In conclusion, with evidence pointing to a multiple-hit model, loss-of-function on itself seems to be insufficient to cause neurodegeneration in C9orf72 ALS/FTD.

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C9orf72 and smcr8 mutant mice reveal MTORC1 activation due to impaired lysosomal degradation and exocytosis

Cited by 43 publications

References 56 publications

C9orf72-associated SMCR8 protein binds in the ubiquitin pathway and with proteins linked with neurological disease

C9orf72-associated SMCR8 protein binds in the ubiquitin pathway and with proteins linked with neurological disease

Cellular and molecular phenotypes ofC9orf72ALS/FTD patient derived iPSC-microglia mono-cultures

C9orf72 loss-of-function: a trivial, stand-alone or additive mechanism in C9 ALS/FTD?

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