The C9orf72-interacting protein Smcr8 is a negative regulator of autoimmunity and lysosomal exocytosis

Zhang, Yingying; Burberry, Aaron; Wang, Jin Yuan; Sandoe, Jackson; Ghosh, Sulagna; Udeshi, Namrata D.; Svinkina, Tanya; Mordes, Daniel A.; Mok, Joanie; Charlton, Maura E.; Li, Quan Zhen; Carr, Steven A.; Eggan, Kevin

doi:10.1101/gad.313932.118

Cited by 68 publications

(63 citation statements)

References 61 publications

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“…It was previously established that C9orf72 is required for the maintenance of normal lysosome function and is itself part of a protein complex that localizes to the cytoplasmic surface of lysosomes when cells are starved of amino acids (Amick et al, 2016; Corrionero and Horvitz, 2018; McAlpine et al, 2018; O’Rourke et al, 2016; Sullivan et al, 2016; Zhang et al, 2018). These observations defined two major questions concerning the pathway in which C9orf72 functions.…”

Section: Discussionmentioning

confidence: 99%

“…Although the repeat expansion results in a reduction in C9orf72 mRNA and protein levels, the extent to which this is relevant for disease pathogenesis remains unclear (Belzil et al, 2013; DeJesus-Hernandez et al, 2011; Gijselinck et al, 2012; Shi et al, 2018; Viodé et al, 2018; Waite et al, 2014; Xi et al, 2013). Nonetheless, investigation of this topic has established that the C9orf72 protein is required for normal lysosome homeostasis in a variety of model systems, including mice, Caenorhabditis elegans , and cultured human cells (Amick et al, 2016; Corrionero and Horvitz, 2018; McAlpine et al, 2018; O’Rourke et al, 2016; Sullivan et al, 2016; Zhang et al, 2018). Thus, beyond potential neurodegenerative disease implications, C9orf72 has an evolutionarily conserved role in supporting lysosome function.…”

Section: Introductionmentioning

confidence: 99%

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PQLC2 recruits the C9orf72 complex to lysosomes in response to cationic amino acid starvation

Amick

Tharkeshwar

Talaia

et al. 2019

Journal of Cell Biology

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The C9orf72 protein is required for normal lysosome function. In support of such functions, C9orf72 forms a heterotrimeric complex with SMCR8 and WDR41 that is recruited to lysosomes when amino acids are scarce. These properties raise questions about the identity of the lysosomal binding partner of the C9orf72 complex and the amino acid–sensing mechanism that regulates C9orf72 complex abundance on lysosomes. We now demonstrate that an interaction with the lysosomal cationic amino acid transporter PQLC2 mediates C9orf72 complex recruitment to lysosomes. This is achieved through an interaction between PQLC2 and WDR41. The interaction between PQLC2 and the C9orf72 complex is negatively regulated by arginine, lysine, and histidine, the amino acids that PQLC2 transports across the membrane of lysosomes. These results define a new role for PQLC2 in the regulated recruitment of the C9orf72 complex to lysosomes and reveal a novel mechanism that allows cells to sense and respond to changes in the availability of cationic amino acids within lysosomes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PQLC2 recruits the C9orf72 complex to lysosomes in response to cationic amino acid starvation

Amick

Tharkeshwar

Talaia

et al. 2019

Journal of Cell Biology

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“…The in vivo phenotypes of SMCR8 deficiency are highly similar to that of C9orf72 deficiency with splenomegaly, inflammation in multiple tissues and autoimmunity, suggesting that C9orf72 and SMCR8 function together as a complex in the hematopoietic system to restrict autoimmunity [29].…”

Section: C9orf72-smcr8 and Immune Regulation 1mentioning

confidence: 93%

SMCR8 negatively regulates AKT and MTORC1 signaling to modulate lysosome biogenesis and tissue homeostasis

Lan

Sullivan

2018

Preprint

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The intronic hexanucleotide expansion in the C9orf72 gene is one of the leading causes of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), 2 devastating neurodegenerative diseases. C9orf72 forms a heterodimer with SMCR8 (Smith-Magenis syndrome chromosome region, candidate 8) protein. However, the physiological function of SMCR8 remains to be characterized. Here we report that ablation of SMCR8 in mice results in splenomegaly with autoimmune phenotypes similar to that of C9orf72 deficiency. Furthermore, SMCR8 loss leads to a drastic decrease of C9orf72 protein levels. Many proteins involved in the macroautophagy-lysosome pathways are downregulated upon SMCR8 loss due to elevated activation of MTORC1 and AKT, which also leads to increased spine density in the Smcr8 knockout neurons. In summary, our studies demonstrate a key role of SMCR8 in regulating MTORC1 and AKT signaling and tissue homeostasis.

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“…The C9ORF72 repeat expansion causes neurodegeneration through loss-and gain-of-function mechanisms [1][2][3]. Reduced C9ORF72 levels alter endosomal trafficking [3,4], autophagy [5,6], and lysosomes in vitro [3,[7][8][9], and increase glutamate receptors on neurons [3]. C9ORF72 ALS/FTD (C9-ALS/FTD) gain-of-function mechanisms include neurotoxic dipeptide repeat proteins (DPRs) generated by repeat-associated non-AUG translation [3,[10][11][12][13][14][15].…”

Section: Main Textmentioning

confidence: 99%

Small molecule inhibition of PIKFYVE kinase rescues gain- and loss-of-functionC9ORF72ALS/FTD disease processesin vivo

Staats

Seah

Sahimi

et al. 2019

Preprint

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The most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide repeat expansion (HRE) in C9ORF72 that contributes to neurodegeneration by both loss-of-function (decreased C9ORF72 protein levels) and gain-offunction (e.g. dipeptide repeat protein production) mechanisms. Although therapeutics targeting the gain-of-function mechanisms are in clinical development, it is unclear if these will be efficacious given the contribution of C9ORF72 loss-of-function processes to neurodegeneration. Moreover, there is a lack of therapeutic strategies for C9ORF72 ALS/FTD with demonstrated efficacy in vivo. Here, we show that small molecule inhibition of PIKFYVE kinase rescues both loss-and gain-of-function C9ORF72 disease mechanisms in vivo. We find that the reduction of C9ORF72 in mouse motor neurons leads to a decrease in early endosomes. In contrast, treatment with the PIKFYVE inhibitor apilimod increases the number of endosomes and lysosomes. We show that reduced C9ORF72 levels increases glutamate receptor levels in hippocampal neurons in mice, and that apilimod treatment rescues this excitotoxicity-related phenotype in vivo. Finally, we show that apilimod also alleviates the gainof-function pathology induced by the C9ORF72 HRE by decreasing levels of dipeptide repeat proteins derived from both sense and antisense C9ORF72 transcripts in hippocampal neurons in vivo. Our data demonstrate the neuroprotective effect of PIKFYVE kinase inhibition in both gain-and loss-of-function murine models of C9ORF72 ALS/FTD. Keywordsamyotrophic lateral sclerosis, frontotemporal dementia, apilimod, C9ORF72, NMDA-induced injury, endosomal trafficking, dipeptide repeat proteins, lysosomes, endosomes, glutamate receptors A. Images of EEA1+ vesicles in the hippocampus of C9-BAC mice treated by direct injection with DMSO or apilimod. Scale bar = 10 µm. B. Number of EEA1+ vesicles per cytosolic area in the hippocampus of C9-BAC mice treated by direct injection with apilimod (n=186 cells from 8 mice) or DMSO (vehicle, n=185 cells from 8 mice) for 48 hours. Mean +/-standard deviation, unpaired t-test. C. Number of EEA1+ vesicles per cytosolic area in the hippocampus of C9-BAC mice treated by direct injection with apilimod (n=8 mice) or DMSO (vehicle, n= 8 mice) for 48 hours. Median +/-interquartile range of cells for each mouse, unpaired t-test comparing mean values per mouse. Horizontal grey dotted line indicates the median number of EEA1+ vesicles per cytosolic area in the hippocampus of C9-BAC mice treated by direct injection with DMSO. D. Images of poly(GP)+ punctae in the hippocampus of C9-BAC mice 48 hours after being treated by direct injection with DMSO or apilimod. Scale bar = 10 µm.E. Number of poly(GP)+ punctae per neuronal area in the hippocampus of C9-BAC mice treated by direct injection with apilimod (n=150 cells from 9 mice) or DMSO (vehicle, n=150 cells from 9 mice) for 48 hours. Control group, included for reference, are untreated wild-type mice (n=125 cells from 6 mice). Median...

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The C9orf72-interacting protein Smcr8 is a negative regulator of autoimmunity and lysosomal exocytosis

Cited by 68 publications

References 61 publications

PQLC2 recruits the C9orf72 complex to lysosomes in response to cationic amino acid starvation

PQLC2 recruits the C9orf72 complex to lysosomes in response to cationic amino acid starvation

SMCR8 negatively regulates AKT and MTORC1 signaling to modulate lysosome biogenesis and tissue homeostasis

Small molecule inhibition of PIKFYVE kinase rescues gain- and loss-of-functionC9ORF72ALS/FTD disease processesin vivo

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