Loss of C9
            <scp>ORF</scp>
            72 impairs autophagy and synergizes with polyQ Ataxin‐2 to induce motor neuron dysfunction and cell death

Sellier, Chantal; Campanari, María-Letizia; Corbier, Camille; Gaucherot, Angéline; Kolb-Cheynel, Isabelle; Oulad‐Abdelghani, Mustapha; Ruffenach, Frank; Page, Adeline; Ciura, Sorana; Kabashi, Edor; Charlet‐Berguerand, Nicolas

doi:10.15252/embj.201593350

Cited by 360 publications

(541 citation statements)

References 126 publications

(202 reference statements)

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“…This uncovers a more direct form of cooperative pathogenesis between gain- and loss-of-function mechanisms in C9ORF72 ALS/FTD. Through a potentially similar mechanism, reduced C9orf72 levels can also facilitate cytoplasmic TDP-43 accumulation in mouse neurons 20 .…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with this hypothesis, elimination of C9orf72 activity alters myeloid cell behavior in mice 14,18,19 and in vitro studies suggest that C9ORF72 activity may enhance autophagy 20,21 .…”

mentioning

confidence: 81%

“…4a, 5b). While previous studies have linked low C9ORF72 levels to changes in vesicle trafficking or autophagy 18,20,30–33 , it remains unknown if loss of C9ORF72 protein directly contributes to degeneration. Thus, we re-expressed C9ORF72 (isoform A or B) in iMNs using a retroviral cassette (Supplementary Fig.…”

Section: C9orf72 Is Haploinsufficient In Alsmentioning

confidence: 98%

“…There are conflicting reports as to whether C9ORF72 levels affect endosomes or lysosomes more significantly, and whether C9ORF72 levels affect vesicle trafficking in neurons in the same way as in cell lines 18,30–33,38,39 . In addition, the functional role of C9ORF72 in patient motor neurons is unclear.…”

Section: Reduced C9orf72 Activity Disrupts Lysosomal Biogenesis In Momentioning

confidence: 99%

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Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons

Shi

Lin

Staats

et al. 2018

Nat Med

495

551

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Summary An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but its pathogenic mechanism remains unclear. Here we use human induced motor neurons (iMNs) to show that repeat-expanded C9ORF72 is haploinsufficient in ALS. We show that C9ORF72 interacts with endosomes and is required for normal vesicle trafficking and lysosomal biogenesis in motor neurons. Repeat expansion reduces C9ORF72 expression, triggering neurodegeneration through two mechanisms: accumulation of glutamate receptors leading to excitotoxicity, and impaired clearance of neurotoxic dipeptide repeat proteins derived from the repeat expansion. Thus, cooperativity between gain- and loss-of-function mechanisms leads to neurodegeneration. Restoring C9ORF72 levels or augmenting its function with constitutively active RAB5 or chemical modulators of RAB5 effectors rescues patient neuron survival and ameliorates neurodegenerative processes in both gain- and loss-of function C9ORF72 mouse models. Thus, modulating vesicle trafficking can rescue neurodegeneration caused by the C9ORF72 repeat expansion. Coupled with rare mutations in ALS2, FIG4, CHMP2B, OPTN, and SQSTM1, our results reveal mechanistic convergence on vesicle trafficking in ALS/FTD.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 81%

Section: C9orf72 Is Haploinsufficient In Alsmentioning

confidence: 98%

Section: Reduced C9orf72 Activity Disrupts Lysosomal Biogenesis In Momentioning

confidence: 99%

See 2 more Smart Citations

Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons

Shi

Lin

Staats

et al. 2018

Nat Med

495

551

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“…It is interesting to note that some DENN domain-containing proteins form hetero-oligomers, such as C9ORF72 and SMCR8 (29,30) and folliculin and folliculin-interacting proteins (31). Here we report for the first time that a DENN domain-containing protein also forms a homo-oligomer.…”

Section: Regulation Of Dennd3mentioning

confidence: 99%

Regulation of DENND3, the exchange factor for the small GTPase Rab12 through an intramolecular interaction

McPherson

2017

Journal of Biological Chemistry

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Edited by Thomas SöllnerThe Rab family of small GTPases functions in multiple aspects of cellular membrane trafficking. Proteins bearing a differentially expressed in normal and neoplastic cells (DENN) domain have emerged as the largest family of Rab-activating guanine nucleotide exchange factors (GEFs). Rab12 functions in the initiation of starvation-induced autophagy, and our previous work revealed that its activator, DENN domain-containing protein 3 (DENND3), is phosphorylated and activated upon starvation. However, how the GEF activity of DENND3 toward Rab12 is regulated at the molecular level is still not understood. Here, we combine size-exclusion chromatography, Förster resonance energy transfer, pulldown, and in vitro GEF assays to demonstrate that regulation of GEF activity is achieved through an intramolecular interaction that is controlled by a key residue in DENND3, tyrosine 940. Our study sheds light on the regulation of Rab12 activation and lays the groundwork for characterizing the regulation of other DENN domain-containing proteins.The Rab family of small GTPases functions in all aspects of cellular membrane trafficking ranging from vesicle budding to transport along the cytoskeleton and fusion with acceptor membranes. Rabs switch between an inactive GDP-bound form and an active GTP-bound form that interacts with effectors to mediate trafficking functions. Guanine nucleotide exchange factors (GEFs) 3 activate Rabs by facilitating the exchange of GDP for GTP (1). There are at least four families of GEFs for Rabs: TRAPP, Rabin8/Sec2, Vps9 domain-containing proteins, and DENN domain-containing proteins (2). With 26 distinct members, DENN domain-containing proteins are the largest family of Rab GEFs (3-8). They are involved in diverse biological functions (4), and mutations in several DENN domain-bearing proteins are linked to human diseases, including the tumor suppressor folliculin associated with Birt-HoggDubé syndrome (9), C9orf72 linked to familial frontotemporal dementia and amyotrophic lateral sclerosis (10, 11), and DENND1B associated with childhood asthma (12).We recently demonstrated that DENN domain-containing protein 3 (DENND3) functions in starvation-induced macroautophagy (13,14). Macroautophagy, which we will hereafter refer to as autophagy, is a conserved cellular process in which various physiological signals, including nutrient starvation, lead to the recruitment of organelles or cytosolic proteins into double membrane vesicles called autophagosomes. The autophagosomes eventually fuse with lysosomes for degradation of the internalized cargo. The resulting building blocks, such as amino acids, are then released back to the cytosol for reuse, helping cells survive starvation. Unc-51-like kinase (ULK) is the most upstream kinase for autophagy initiation (15). Upon starvation, ULK phosphorylates DENND3 at Ser-554 and Ser-572, recruiting the adapter protein 14-3-3, and this process leads to up-regulation of DENND3 GEF activity toward its substrate Rab12. Rab12 on recycling endosomes (1...

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TCR signalling network organization at the immunological synapses of murine regulatory T cells

et al. 2017

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Regulatory T (Treg) cells require T-cell receptor (TCR) signalling to exert their immunosuppressive activity, but the precise organization of the TCR signalling network compared to conventional T (Tconv) cells remains elusive. By using accurate mass spectrometry and multi-epitope ligand cartography (MELC) we characterized TCR signalling and recruitment of TCR signalling components to the immunological synapse (IS) in www.eji-journal.euThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 2Marco van Ham et al. Eur. J. Immunol. 2017. 0: 1-16 in Treg cells, thereby, seems to be differentially organized as in Tconv cells: Treg cells show reduced Ca 2+ flux and ERK1/2 phosphorylation upon TCR stimulation [6][7][8], and downstream signalling molecules such as Lck, LAT and PLCγ1 are essential for Treg cell suppressive capacity [9,10]. In this line, a novel TCRmediated ADAP/integrin-independent PLCγ1 activation pathway was described to be required for suppression of Tconv cells by Treg cells [11]. Furthermore, Treg cells exhibit reduced S473 phosphorylation of Akt which seems a prerequisite for suppression [12]. Although the enzymatic activity of the tyrosine kinase ZAP70 seems to be dispensable for the suppressive phenotype of Foxp3 + Treg cells [13], a single mutation within the SH2-domain of ZAP70 leads to impaired suppressive activities, which indicated its importance at the immunological synapse (IS) [14]. Finally, it has only recently been recognized that the recruitment of TCR signalling components into the IS is differentially organized in Treg cells and Tconv cells. The protein kinase PKCθ is recruited to the IS in Tconv cells, in Treg cells, however, this kinase was found to be sequestered away from the IS, but still of importance to control suppression [15]. The spatial recruitment of signalling components during IS formation critically depends on cytoskeleton dynamics, which in turn is controlled by TCR activation and subsequent phosphorylation of proteins regulating cytoskeleton reorganization [5]. As part of these processes the microtubule-organizing centre (MTOC) is rapidly translocated in proximity to the IS. MTOC repositioning depends on LAT, ZAP70 and SLP76 [16] and is regulated by a cascade of distinct isoforms of the family of novel protein kinase C (nPKC) [17]. The MTOC serves as a platform to coordinate molecular movements from and to the IS through the support of microtubule (MT) motors [18]. For instance, TCR microclusters move along MTs towards the centre of the IS in a dynein-dependent manner [19], and hindrance of MTOC polarization, molecular transport and cytoskeleton dynamics prevent proper propagation of TCR signals [20].It is now tempting to speculate that the localization of signalling modules within the IS may be instrumental for the formation of a Treg cell-specific IS and the suppressive phenotype of Treg cells. At this moment, however,...

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Loss of C9 ORF 72 impairs autophagy and synergizes with polyQ Ataxin‐2 to induce motor neuron dysfunction and cell death

Cited by 360 publications

References 126 publications

Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons

Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons

Regulation of DENND3, the exchange factor for the small GTPase Rab12 through an intramolecular interaction

TCR signalling network organization at the immunological synapses of murine regulatory T cells

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