Cellular and physiological functions of C9ORF72 and implications for ALS/FTD

Pang, Weilun; Hu, Fenghua

doi:10.1111/jnc.15255

Cited by 57 publications

(58 citation statements)

References 155 publications

(345 reference statements)

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“…Our data strongly support that C9orf72:SMCR8 is a GAP for ARF GTPases. Given the report that C9orf72:SMCR8 is also a GAP for RAB8A and RAB11A 20 , the question as to what are the physiological substrates of C9orf72:SMCR8 has become important in C9ORF72, ALS, and FTD research 38,39 . The data presented here affirm C9orf72:SMCR8 as a bona fide ARF GAP by presenting a well-ordered cryo-EM structure which makes verifiable predictions of the activity of point mutants of both ARF1 and C9orf72.…”

Section: Discussionmentioning

confidence: 99%

Structural basis for the ARF GAP activity and specificity of the C9orf72 complex

Fromm

Remis

et al. 2021

Preprint

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Mutation of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontal temporal degeneration (FTD), which is attributed to both a gain and loss of function. C9orf72 forms a complex with SMCR8 and WDR41, which was reported to have GTPase activating protein activity toward ARF proteins, RAB8A, and RAB11A. We determined the cryo-EM structure of ARF1-GDP-BeF3- bound to C9orf72:SMCR8:WDR41. The SMCR8longin and C9orf72longin domains form the binding pocket for ARF1. One face of the C9orf72longin domain holds ARF1 in place, while the SMCR8longin positions the catalytic finger Arg147 in the ARF1 active site. Mutations in interfacial residues of ARF1 and C9orf72 reduced or eliminated GAP activity. RAB8A GAP required ~10-fold higher concentrations of the C9orf72 complex than for ARF1. These data support a specific function for the C9orf72 complex as an ARF GAP.

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Section: Discussionmentioning

confidence: 99%

Structural basis for the ARF GAP activity and specificity of the C9orf72 complex

Fromm

Remis

et al. 2021

Preprint

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“…The Chromosome 9 Open Reading Frame 72 (C9ORF72) gene contains 12 exons and encodes for a little characterized protein that has a pivotal role in autophagy modulation, recently described as part of a guanine nucleotide exchange factor complex [ 50 , 51 ]. In a healthy condition, the hexanucleotide GGGGCC (G 4 C 2 ) within the first intron may be repeated from 2 to 23 times but its aberrant expansion reaching hundreds or thousands of repeats has been found in ALS and FTD patients and is considered the most common genetic cause of fALS.…”

Section: Als: An Old But Unbeaten Diseasementioning

confidence: 99%

Where and Why Modeling Amyotrophic Lateral Sclerosis

Liguori

Amadio

Volonté

2021

IJMS

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Over the years, researchers have leveraged a host of different in vivo models in order to dissect amyotrophic lateral sclerosis (ALS), a neurodegenerative/neuroinflammatory disease that is heterogeneous in its clinical presentation and is multigenic, multifactorial and non-cell autonomous. These models include both vertebrates and invertebrates such as yeast, worms, flies, zebrafish, mice, rats, guinea pigs, dogs and, more recently, non-human primates. Despite their obvious differences and peculiarities, only the concurrent and comparative analysis of these various systems will allow the untangling of the causes and mechanisms of ALS for finally obtaining new efficacious therapeutics. However, harnessing these powerful organisms poses numerous challenges. In this context, we present here an updated and comprehensive review of how eukaryotic unicellular and multicellular organisms that reproduce a few of the main clinical features of the disease have helped in ALS research to dissect the pathological pathways of the disease insurgence and progression. We describe common features as well as discrepancies among these models, highlighting new insights and emerging roles for experimental organisms in ALS.

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“…Currently, intronic HRE in the C9orf72 gene represents the most common genetic cause of ALS [ 23 ]. C9orf72 is part of a guanine nucleotide exchange factor complex [ 24 ], whose precise function remains unclear, but which was shown to be an important regulator of membrane trafficking and autophagy [ 25 ]. Lastly, FUS and TARDBP encode two DNA/RNA-binding proteins, which play distinct roles in transcription, as well as numerous roles in RNA metabolism, including splicing, stability, and transport [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Amyotrophic Lateral Sclerosis Genes in Drosophila melanogaster

Layalle

They

Ourghani

et al. 2021

IJMS

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Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disease characterized by the progressive degeneration of upper and lower motoneurons. Most ALS cases are sporadic but approximately 10% of ALS cases are due to inherited mutations in identified genes. ALS-causing mutations were identified in over 30 genes with superoxide dismutase-1 (SOD1), chromosome 9 open reading frame 72 (C9orf72), fused in sarcoma (FUS), and TAR DNA-binding protein (TARDBP, encoding TDP-43) being the most frequent. In the last few decades, Drosophila melanogaster emerged as a versatile model for studying neurodegenerative diseases, including ALS. In this review, we describe the different Drosophila ALS models that have been successfully used to decipher the cellular and molecular pathways associated with SOD1, C9orf72, FUS, and TDP-43. The study of the known fruit fly orthologs of these ALS-related genes yielded significant insights into cellular mechanisms and physiological functions. Moreover, genetic screening in tissue-specific gain-of-function mutants that mimic ALS-associated phenotypes identified disease-modifying genes. Here, we propose a comprehensive review on the Drosophila research focused on four ALS-linked genes that has revealed novel pathogenic mechanisms and identified potential therapeutic targets for future therapy.

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Cellular and physiological functions of C9ORF72 and implications for ALS/FTD

Cited by 57 publications

References 155 publications

Structural basis for the ARF GAP activity and specificity of the C9orf72 complex

Structural basis for the ARF GAP activity and specificity of the C9orf72 complex

Where and Why Modeling Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis Genes in Drosophila melanogaster

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