C9ORF72 (9p21.2), SMRC8 (17p11.2) ja WDR41 (5q13.3-q14.1) lysosomaalista yhteistyötä aivojen joustavan reletoiminnan taustalla

https://www.ncbi.nlm.nih.gov/gene/203228

Official Symbol

C9orf72

Official Full Name

C9orf72-SMCR8 complex subunit

Also known as

ALSFTD; DENND9; FTDALS; DENNL72; FTDALS1

Summary

The protein encoded by this gene plays an important role in the regulation of endosomal trafficking, and has been shown to interact with Rab proteins that are involved in autophagy and endocytic transport. Expansion of a GGGGCC nucleoide  repeat from 2-22 copies to 700-1600 copies in the intronic sequence between alternate 5' exons in transcripts from this gene is associated with 9p-linked ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia) (PMID: 21944778, 21944779).

 Studies suggest that hexanucleotide expansions could result in the selective stabilization of repeat-containing pre-mRNA, and the accumulation of insoluble dipeptide  (WD containing) repeat protein aggregates that could be pathogenic in FTD-ALS patients (PMID: 23393093). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2016]

Expression  Ubiquitous expression in appendix (RPKM 9.7), testis (RPKM 9.3) and 25 other tissues See more   Orthologs mouse all

Preferred Names

guanine nucleotide exchange C9orf72

Names

protein C9orf72

https://www.ncbi.nlm.nih.gov/protein/NP_001242983.1 

 

The G-rich Repeats in FMR1 and C9orf72 Loci Are Hotspots for Local
            Unpairing of DNA.

The C9orf72 GGGGCC repeat is translated into aggregating
            dipeptide-repeat proteins in FTLD/ALS

ORIGIN      
        1 mstlcpppsp avakteials gkspllaatf aywdnilgpr vrhiwapkte qvllsdgeit
       61 flanhtlnge ilrnaesgai dvkffvlsek gviivslifd gnwngdrsty glsiilpqte
      121 lsfylplhrv cvdrlthiir kgriwmhker qenvqkiile gtermedqgq siipmltgev
      181 ipvmellssm kshsvpeeid iadtvlnddd igdschegfl lnaisshlqt cgcsvvvgss
      241 aekvnkivrt lclfltpaer kcsrlceaes sfkyesglfv qgllkdstgs fvlpfrqvmy
      301 apyptthidv dvntvkqmpp chehiynqrr ymrseltafw ratseedmaq dtiiytdesf
      361 tpdlnifqdv lhrdtlvkaf ldqvfqlkpg lslrstflaq fllvlhrkal tlikyieddt
      421 qkgkkpfksl rnlkidldlt aegdlniima laekikpglh sfifgrpfyt svqerdvlmt
      481 f
//

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202986/figure/F4/

 

 

 

 

 

Conserved Domains (1) summary

pfam15019
Location:61 → 324

C9orf72-like; C9orf72-like protein family 

The precise function of this family is unknown but members have been found to be localized in the cytoplasm of brain tissue. Defects in the gene, C9orf72, are the cause of frontotemporal dementia and/or amyotrophic lateral sclerosis (FTDALS) which is an autosomal dominant neurodegenerative disorder. The disorder is caused by a large expansion of a GGGGCC hexa-nucleotide within the first C9orf72 intron located between the first and the second non-coding exons. The expansion leads to the loss of transcription of one of the two transcripts encoding isoform 1 and to the formation of nuclear RNA foci. This domain family is found in eukaryotes, and is typically between 230 and 250 amino acids in length. There is a single completely conserved residue F that may be functionally important.

• Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.Neuron 2011 Oct 20; 72(2):245-56

Related articles in PubMed

1. FDG-PET underscores the key role of the thalamus in frontotemporal lobar degeneration caused by C9ORF72 mutations. Diehl-Schmid J, et al. Transl Psychiatry, 2019 Jan 31. PMID 30705258, Free PMC Article
2. Phenotypic variability and neuropsychological findings associated with C9orf72 repeat expansions in a Bulgarian dementia cohort. Mehrabian S, et al. PLoS One, 2018. PMID 30550541, Free PMC Article
3. C9orf72, a protein associated with amyotrophic lateral sclerosis (ALS) is a guanine nucleotide exchange factor. Iyer S, et al. PeerJ, 2018. PMID 30356970, Free PMC Article 
4. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two late onset neurodegenerative diseases, have been shown to share overlapping cellular pathologies and genetic origins. Studies suggest that a hexanucleotide repeat expansion in the first intron of the C9orf72 gene is the most common cause of familial FTD and ALS pathology. The C9orf72 protein is predicted to be a differentially expressed in normal and neoplastic cells domain protein implying that C9orf72 functions as a guanine nucleotide exchange factor (GEF) to regulate specific Rab GTPases. Reported studies thus far point to a putative role for C9orf72 in lysosome biogenesis, vesicular trafficking, autophagy and mechanistic target of rapamycin complex1 (mTORC1) signaling. Here we report the expression, purification and biochemical characterization of C9orf72 protein. We conclusively show that C9orf72 is a GEF. The distinctive presence of both Rab- and Rho-GTPase GEF activities suggests that C9orf72 may function as a dual exchange factor coupling physiological functions such as cytoskeleton modulation and autophagy with endocytosis.
5. The Emerging Role of DNA Damage in the Pathogenesis of the C9orf72 Repeat Expansion in Amyotrophic Lateral Sclerosis. Konopka A, et al. Int J Mol Sci, 2018 Oct 12. PMID 30322030, Free PMC Article Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressing neurodegenerative disease affecting motor neurons, and frontotemporal dementia (FTD) is a behavioural disorder resulting in early-onset dementia. Hexanucleotide (G4C2) repeat expansions in the gene encoding chromosome 9 open reading frame 72 (C9orf72) are the major cause of familial forms of both ALS (~40%) and FTD (~20%) worldwide. The C9orf72 repeat expansion is known to form abnormal nuclei acid structures, such as hairpins, G-quadruplexes, and R-loops, which are increasingly associated with human diseases involving microsatellite repeats. These configurations form during normal cellular processes, but if they persist they also damage DNA, and hence are a serious threat to genome integrity. It is unclear how the repeat expansion in C9orf72 causes ALS, but recent evidence implicates DNA damage in neurodegeneration. This may arise from abnormal nucleic acid structures, the greatly expanded C9orf72 RNA, or by repeat-associated non-ATG (RAN) translation, which generates toxic dipeptide repeat proteins. In this review, we detail recent advances implicating DNA damage in C9orf72-ALS. Furthermore, we also discuss increasing evidence that targeting these aberrant C9orf72 confirmations may have therapeutic value for ALS, thus revealing new avenues for drug discovery for this disorder.
6. C9orf72 Protein Plasmatic Concentrations Are Similar between C9ORF72 Expansion Carriers and Noncarriers in Frontotemporal Dementia. Fourier A, et al. Dement Geriatr Cogn Disord, 2018. PMID 30261505

See all (381) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

 

GeneRIFs: Gene References Into Functions

1. Study compared cerebral glucose metabolism of C9-familial frontotemporal lobar degeneration patients with matched non-carriers and with healthy controls (HCs). Voxel-based comparisons revealed a significant hypometabolic pattern in mutation carriers relative to HCs across widespread frontal and temporal areas, cingulate cortex, Rolandic operculum, caudate nuclei, and thalami.
2. In the present study identified patients of SCA(spinocerebellar ataxia) 1, 2, 3, and 6 who also carried pathogenic C9orf72 repeat expansions.
3. This study demonstrated that in presynaptic localization of C9orf72 protein and reduced protein levels in C9orf72 mutation carriers.
4. The expression levels of HSF1 and protein chaperones are increased in C9ORF72-ALS/FTLD patients and in gain-of-function model systems.
5. Study is the first report of a pair of amyotrophic lateral sclerosis -concordant dizygotic twins carrying a C9orf72 G4C2 expansion probably of intermediate length, and with a detailed clinical and genetic characterization.
6. Restoring C9ORF72 levels or augmenting its function with constitutively active RAB5 or chemical modulators of RAB5 effectors rescued patient neuron survival and ameliorated neurodegenerative processes in both gain- and loss-of-function C9ORF72 mouse models.
7. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 dipeptide-repeat (DPR) protein toxicity in cells. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of induced motor neurons from patients with C9ORF72 ALS.
8. The report confirms the notion that C9orf72 repeat expansions underlie a broad spectrum of neurodegenerative phenotypes. Relatively isolated agraphia in two cases with C9orf72 repeat expansions is a strong motivation to provide detailed and sophisticated oral and written language assessments that can be used to more precisely characterize early cognitive deficits in these heterogeneous conditions.
9. Downregulation of C9orf72 in non-neuronal human cells overexpressing amyloid-beta protein precursor (AbetaPP) resulted in increased levels of secreted AbetaPP fragments and Abeta, while levels of AbetaPP or its C-terminal fragments (CTFs) remained unchanged. In neuronal cells, AbetaPP and C83 CTF levels were decreased upon C9orf72 knockdown, but those of secreted AbetaPP fragments or Abeta remained unchanged.
10. Four of the ALS patients in this study possessed an expansion of the C9ORF72 gene, which has been linked to the presence of electrophysiological brain abnormalities, including cortical hyperexcitability, background rhythm slowing, and epileptic activity

Submit: New GeneRIF Correction See all GeneRIFs (350)

SMCR8 (17p11.2),https://www.ncbi.nlm.nih.gov/gene/140775
 DENND8A, SMCR8-C9ORF72  alayksikkö, subunit

Official Symbol

SMCR8

Official Full Name

SMCR8-C9orf72 complex subunit

Also known as

DENND8A

Expression

Ubiquitous expression in bone marrow (RPKM 10.7), spleen (RPKM 8.2) and 25 other tissues See more Ortholog  mouse all

Related articles in PubMed

1. Discovery of Novel DENN Proteins: Implications for the Evolution of Eukaryotic Intracellular Membrane Structures and Human Disease. Zhang D, et al. Front Genet, 2012. PMID 23248642, Free PMC ArticleThe tripartite DENN module, comprised of a N-terminal longin domain, followed by DENN, and d-DENN domains, is a GDP-GTP exchange factor (GEFs) for Rab GTPases, which are regulators of practically all membrane trafficking events in eukaryotes. Using sequence and structure analysis we identify multiple novel homologs of the DENN module, many of which can be traced back to the ancestral eukaryote. These findings provide unexpected leads regarding key cellular processes such as autophagy, vesicle-vacuole interactions, chromosome segregation, and human disease. Of these, SMCR8, the folliculin interacting protein-1 and 2 (FNIP1 and FNIP2), nitrogen permease regulator 2 (NPR2), and NPR3 are proposed to function in recruiting Rab GTPases during different steps of autophagy, fusion of autophagosomes with the vacuole and regulation of cellular metabolism. Another novel DENN protein identified in this study is C9ORF72; expansions of the hexanucleotide GGGGCC in its first intron have been recently implicated in amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD). While this mutation is proposed to cause a RNA-level defect, the identification of C9ORF72 as a potential DENN-type GEF raises the possibility that at least part of the pathology might relate to a specific Rab-dependent vesicular trafficking process, as has been observed in the case of some other neurological conditions with similar phenotypes. We present evidence that the longin domain, such as those found in the DENN module, are likely to have been ultimately derived from the related domains found in prokaryotic GTPase-activating proteins of MglA-like GTPases. Thus, the origin of the longin domains from this ancient GTPase-interacting domain, concomitant with the radiation of GTPases, especially of the Rab clade, played an important role in the dynamics of eukaryotic intracellular membrane systems.
2. C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling. Amick J, et al. Mol Biol Cell, 2016 Oct 15. PMID 27559131, Free PMC Article  Hexanucleotide expansion in an intron of the C9orf72 gene causes amyotrophic lateral sclerosis and frontotemporal dementia. However, beyond bioinformatics predictions that suggested structural similarity to folliculin, the Birt-Hogg-Dubé syndrome tumor suppressor, little is known about the normal functions of the C9orf72 protein. To address this problem, we used genome-editing strategies to investigate C9orf72 interactions, subcellular localization, and knockout (KO) phenotypes. We found that C9orf72 robustly interacts with SMCR8 (a protein of previously unknown function). We also observed that C9orf72 localizes to lysosomes and that such localization is negatively regulated by amino acid availability. Analysis of C9orf72 KO, SMCR8 KO, and double-KO cell lines revealed phenotypes that are consistent with a function for C9orf72 at lysosomes. These include abnormally swollen lysosomes in the absence of C9orf72 and impaired responses of mTORC1 signaling to changes in amino acid availability (a lysosome-dependent process) after depletion of either C9orf72 or SMCR8. Collectively these results identify strong physical and functional interactions between C9orf72 and SMCR8 and support a lysosomal site of action for this protein complex.
3. The C9orf72-interacting protein Smcr8 is a negative regulator of autoimmunity and lysosomal exocytosis. Zhang Y, et al. Genes Dev, 2018 Jul 1. PMID 29950492, While a mutation in C9ORF72 is the most common genetic contributor to amyotrophic lateral sclerosis (ALS), much remains to be learned concerning the function of the protein normally encoded at this locus. To elaborate further on functions for C9ORF72, we used quantitative mass spectrometry-based proteomics to identify interacting proteins in motor neurons and found that its long isoform complexes with and stabilizes SMCR8, which further enables interaction with WDR41. To study the organismal and cellular functions for this tripartite complex, we generated Smcr8 loss-of-function mutant mice and found that they developed phenotypes also observed in C9orf72 loss-of-function animals, including autoimmunity. Along with a loss of tolerance for many nervous system autoantigens, we found increased lysosomal exocytosis in Smcr8 mutant macrophages. In addition to elevated surface Lamp1 (lysosome-associated membrane protein 1) expression, we also observed enhanced secretion of lysosomal components-phenotypes that we subsequently observed in C9orf72 loss-of-function macrophages. Overall, our findings demonstrate that C9ORF72 and SMCR8 have interdependent functions in suppressing autoimmunity as well as negatively regulating lysosomal exocytosis-processes of potential importance to ALS.
4. Multiplex image-based autophagy RNAi screening identifies SMCR8 as ULK1 kinase (unc-51 like autophagy activating kinase 1)  activity and gene expression regulator. Jung J, et al. Elife, 2017 Feb 14. PMID 28195531, Free PMC Article
5. The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway. Sullivan PM, et al. Acta Neuropathol Commun, 2016 May 18. PMID 27193190,* Free PMC Article   .. Here we report the identification of two binding partners of C9orf72: SMCR8 and WDR41. We show that WDR41 interacts with the C9orf72/SMCR8 heterodimer and WDR41 is tightly associated with the Golgi complex. We further demonstrate that C9orf72/SMCR8/WDR41 associates with the FIP200/Ulk1 complex, which is essential for autophagy initiation  (OBS.*  FREE ARTICLE highlights well!)

See all (22) citations in PubMed

GeneRIFs: Gene References Into Functions

1. While focusing on the role of SMCR8 during autophagy initiation, we found that kinase activity and gene expression of ULK1 are increased upon SMCR8 depletion. The latter phenotype involved association of SMCR8 with the ULK1 gene locus.
2. Study describes the identification of two binding partners for C9orf72: SMCR8 and WDR41 and demonstrated that C9orf72/SMCR8/WDR41 interacts with the FIP200/Ulk1/ATG13/ATG101 complex.

*The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway.

Sullivan PM¹, Zhou X¹, Robins AM¹, Paushter DH¹, Kim D¹, Smolka MB¹, Hu F². Abstract

Hexanucleotide repeat expansion in the C9orf72 gene is a leading cause of frontotemporal lobar degeneration (FTLD) with amyotrophic lateral sclerosis (ALS). Reduced expression of C9orf72 has been proposed as a possible disease mechanism. However, the cellular function of C9orf72 remains to be characterized. Here we report the identification of two binding partners of C9orf72: SMCR8 and WDR41. We show that WDR41 interacts with the C9orf72/SMCR8 heterodimer and WDR41 is tightly associated with the Golgi complex. We further demonstrate that C9orf72/SMCR8/WDR41 associates with the FIP200/Ulk1 complex, which is essential for autophagy initiation. C9orf72 deficient mice, generated using the CRISPR/Cas9 system, show severe inflammation in multiple organs, including lymph node, spleen and liver. Lymph node enlargement and severe splenomegaly are accompanied with macrophage infiltration. Increased levels of autophagy and lysosomal proteins and autophagy defects were detected in both the spleen and liver of C9orf72 deficient mice, supporting an in vivo role of C9orf72 in regulating the autophagy/lysosome pathway. In summary, our study elucidates potential physiological functions of C9orf72 and disease mechanisms of ALS/FTLD. KEYWORDS:

Amyotrophic lateral sclerosis; Autophagy; C9orf72; FIP200/RB1CC1; Frontotemporal lobar degeneration; Lysosome; SMCR8; Ulk1; WDR41


(KUVASSA näkyy tripartiitti kompleksi: C9ORFt2-SMCR8-WDR41): 

 

WDR41 (5q13.3-14.1), WD repeat  domain 41,  MISTP048 
 https://www.ncbi.nlm.nih.gov/gene/55255

Official Full Name WD repeat domain 41provided by HGNC

Gene type protein coding

Also known as MSTP048

ExpressionUbiquitous expression in thyroid (RPKM 15.6), brain (RPKM 8.1) and 25 other tissues See more Orthologs mouse all

 

(Tässä on linkki jonka avulla pystyy tarkkailemaan kaikki  wd- domaanit alla olevasta proteiinista.)

https://www.ncbi.nlm.nih.gov/protein/NP_060738.2 

 

ORIGIN      
        1 mlrwligggr epqglaeksp lqtigeeqtq npytellvlk ahhdivrflv qlddyrfasa
       61 gddgivvvwn aqtgekllel nghtqkitai itfpslesce eknqliltas adrtvivwdg
      121 dttrqvqris cfqstvkclt vlqrldvwls ggndlcvwnr kldllcktsh lsdtgisalv
      181 eipkncvvaa vgkeliifrl vaptegslew dilevkrlld hqdnilslin vndlsfvtgs
      241 hvgeliiwda ldwtmqayer nfwdpspqld tqqeiklcqk sndisihhft cdeenvfaav
      301 grglyvyslq mkrviacqkt ahdsnvlhva rlpnrqlisc sedgsvriwe lrekqqlaae
      361 pvptgffnmw gfgrvskqas qpvkkqqena tscsleligd lighsssvem flyfedhglv
      421 tcsadhliil wkngeresgl rslrlfqkle engdlylav
//

 

Conserved Domains (2) summary

sd00039
Location:88 → 131

7WD40; WD40 repeat [structural motif] 

WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from its N-terminus and the WD dipeptide at its C-terminus and is 40 residues long, hence the name WD40; between GH and WD lies a conserved core; serves as a stable propeller-like platform to which proteins can bind either stably or reversibly; forms a propeller-like structure with several blades where each blade is composed of a four-stranded anti-parallel b-sheet; instances with few detectable copies are hypothesized to form larger structures by dimerization; each WD40 sequence repeat forms the first three strands of one blade and the last strand in the next blade; the last C-terminal WD40 repeat completes the blade structure of the first WD40 repeat to create the closed ring propeller-structure; residues on the top and bottom surface of the propeller are proposed to coordinate interactions with other proteins and/or small ligands; 7 copies of the repeat are present in this alignment.

cl25539
Location:38 → 350

WD40; WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from ..

Related articles in PubMed

1. WDR41 supports lysosomal response to changes in amino acid availability. Amick J, et al. Mol Biol Cell, 2018 Sep 1. PMID 29995611, Free PMC Article
2. Discovery and replication of dopamine-related gene effects on caudate volume in young and elderly populations (N=1198) using genome-wide search. Stein JL, et al. Mol Psychiatry, 2011 Sep. PMID 21502949, Free PMC Article
3. Multiplex image-based autophagy RNAi screening identifies SMCR8 as ULK1 kinase activity and gene expression regulator. Jung J, et al. Elife, 2017 Feb 14. PMID 28195531, Free PMC ArticleAutophagy is an intracellular recycling and degradation pathway that depends on membrane trafficking. Rab GTPases are central for autophagy but their regulation especially through the activity of Rab GEFs remains largely elusive. We employed a RNAi screen simultaneously monitoring different populations of autophagosomes and identified 34 out of 186 Rab GTPase, GAP and GEF family members as potential autophagy regulators, amongst them SMCR8. SMCR8 uses overlapping binding regions to associate with C9ORF72 or with a C9ORF72-ULK1 kinase complex holo-assembly, which function in maturation and formation of autophagosomes, respectively. While focusing on the role of SMCR8 during autophagy initiation, we found that kinase activity and gene expression of ULK1 are increased upon SMCR8 depletion. The latter phenotype involved association of SMCR8 with the ULK1 gene locus. Global mRNA expression analysis revealed that SMCR8 regulates transcription of several other autophagy genes including WIPI2. Collectively, we established SMCR8 as multifaceted negative autophagy regulator   (Suom. kommentti: WIPI2:sta kirjoitan Phytin blogiini: https://www.ncbi.nlm.nih.gov/gene/26100,   Etsin  tänään yhteisnimittäjää näille WD- proteiineille) 
4. The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway. Sullivan PM, et al. Acta Neuropathol Commun, 2016 May 18. PMID 27193190, Free PMC Article
5. Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death. Sellier C, et al. EMBO J, 2016 Jun 15. PMID 27103069, Free PMC Article An intronic expansion of GGGGCC repeats within the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). Ataxin-2 with intermediate length of polyglutamine expansions (Ataxin-2 Q30x) is a genetic modifier of the disease. Here, we found that C9ORF72 forms a complex with the WDR41 and SMCR8 proteins to act as a GDP/GTP exchange factor for RAB8a and RAB39b and to thereby control autophagic flux. Depletion of C9orf72 in neurons partly impairs autophagy and leads to accumulation of aggregates of TDP-43 and P62 proteins, which are histopathological hallmarks of ALS-FTD. SMCR8 is phosphorylated by TBK1 and depletion of TBK1 can be rescued by phosphomimetic mutants of SMCR8 or by constitutively active RAB39b, suggesting that TBK1, SMCR8, C9ORF72, and RAB39b belong to a common pathway regulating autophagy. While depletion of C9ORF72 only has a partial deleterious effect on neuron survival, it synergizes with Ataxin-2 Q30x toxicity to induce motor neuron dysfunction and neuronal cell death. These results indicate that partial loss of function of C9ORF72 is not deleterious by itself but synergizes with Ataxin-2 toxicity, suggesting a double-hit pathological mechanism in ALS-FTD. 

Tässä kohdassa on pääasiassa tripartiittikompleksista:
1) C9orf72
2) sen kanssa heterodimeerin tekevästä  SMCR8
ja kun ne ovat funktiossaan lysosomissa,
3)  niitten kansa tekee interaktion  WD-toistodomaaneja omaava WDR41.
Nämä ovat kaikki eri kromosomeista.