scholarly journals The C9orf72 repeat expansion disrupts nucleocytoplasmic transport

Nature ◽  
2015 ◽  
Vol 525 (7567) ◽  
pp. 56-61 ◽  
Author(s):  
Ke Zhang ◽  
Christopher J. Donnelly ◽  
Aaron R. Haeusler ◽  
Jonathan C. Grima ◽  
James B. Machamer ◽  
...  
Keyword(s):  
Nucleocytoplasmic Transport ◽  
Repeat Expansion ◽  
C9orf72 Repeat Expansion

scholarly journals Toxic PR poly-dipeptides encoded by the C9orf72 repeat expansion target Kapβ2 and dysregulate phase separation of low-complexity domains

2019 ◽  
Author(s):  
Hitoki Nanaura ◽  
Honoka Kawamukai ◽  
Ayano Fujiwara ◽  
Takeru Uehara ◽  
Mari Nakanishi ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Nuclear Transport ◽  
Low Complexity ◽  
Nucleocytoplasmic Transport ◽  
Repeat Expansion ◽  
C9orf72 Repeat Expansion ◽  
Fused In Sarcoma ◽  
Transport Receptors ◽  
Localization Signal ◽  
Competing Interaction

ABSTRACTLow-complexity (LC) domains of proteins are found in about one fifth of human proteome, and a group of LC-domains form labile cross-β polymers and liquid-like droplets. Polymers and droplets formed from LC-domains are dynamically regulated by posttranslational modifications and molecular chaperones including nuclear transport receptors. Repeat expansion in the first intron of a gene designated C9orf72, which is the most prevalent form of familial amyotrophic lateral sclerosis (ALS), causes nucleocytoplasmic transport deficit, however, the detailed mechanism remains unsolved. Here we show that the proline:arginine (PR) poly-dipeptides encoded by the C9orf72 repeat expansion bound nuclear transport receptor Kapβ2 through its nuclear localization signal (NLS) recognition motif, and inhibited the ability of Kapβ2 to melt fused in sarcoma (FUS) droplets by competing interaction with FUS. The findings in this study offer mechanistic insights as to how the C9orf72 repeat expansion disables nucleocytoplasmic transport and causes neurodegenerative diseases.

scholarly journals The Emerging Role of DNA Damage in the Pathogenesis of the C9orf72 Repeat Expansion in Amyotrophic Lateral Sclerosis

2018 ◽  
Vol 19 (10) ◽  
pp. 3137 ◽  
Author(s):  
Anna Konopka ◽  
Julie Atkin
Keyword(s):  
Dna Damage ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Repeat Expansion ◽  
Chromosome 9 ◽  
Gene Encoding ◽  
C9orf72 Repeat Expansion ◽  
Reading Frame ◽  
Early Onset Dementia ◽  
Lateral Sclerosis

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.

scholarly journals C9ORF72 Repeat Expansion Affects the Proteome of Primary Skin Fibroblasts in ALS

2021 ◽  
Vol 22 (19) ◽  
pp. 10385
Author(s):  
Marta Lualdi ◽  
Adeena Shafique ◽  
Edoardo Pedrini ◽  
Luisa Pieroni ◽  
Viviana Greco ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Interaction Network ◽  
Enrichment Analysis ◽  
Repeat Expansion ◽  
Skin Fibroblasts ◽  
Chromosome 9 ◽  
Functional Enrichment ◽  
Molecular Pathways ◽  
C9orf72 Repeat Expansion ◽  
Als Patients

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of the corticospinal motor neurons, which ultimately leads to death. The repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) represents the most common genetic cause of ALS and it is also involved in the pathogenesis of other neurodegenerative disorders. To offer insights into C9ORF72-mediated pathogenesis, we quantitatively analyzed the proteome of patient-derived primary skin fibroblasts from ALS patients carrying the C9ORF72 mutation compared with ALS patients who tested negative for it. Differentially expressed proteins were identified, used to generate a protein-protein interaction network and subjected to a functional enrichment analysis to unveil altered molecular pathways. ALS patients were also compared with patients affected by frontotemporal dementia carrying the C9ORF72 repeat expansion. As a result, we demonstrated that the molecular pathways mainly altered in fibroblasts (e.g., protein homeostasis) mirror the alterations observed in C9ORF72-mutated neurons. Moreover, we highlighted novel molecular pathways (nuclear and mitochondrial transports, vesicle trafficking, mitochondrial bioenergetics, glucose metabolism, ER-phagosome crosstalk and Slit/Robo signaling pathway) which might be further investigated as C9ORF72-specific pathogenetic mechanisms. Data are available via ProteomeXchange with the identifier PXD023866.

scholarly journals C9ORF72 Repeat Expansion in Amyotrophic Lateral Sclerosis in the Kii Peninsula of Japan

2012 ◽  
Vol 69 (9) ◽  
Author(s):  
Hiroyuki Ishiura ◽  
Yuji Takahashi ◽  
Jun Mitsui ◽  
Sohei Yoshida ◽  
Tameko Kihira ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Repeat Expansion ◽  
Kii Peninsula ◽  
C9orf72 Repeat Expansion ◽  
Lateral Sclerosis

Mixed tau, TDP-43 and p62 pathology in FTLD associated with a C9ORF72 repeat expansion and p.Ala239Thr MAPT (tau) variant

2012 ◽  
Vol 125 (2) ◽  
pp. 303-310 ◽  
Author(s):  
Andrew King ◽  
Safa Al-Sarraj ◽  
Claire Troakes ◽  
Bradley N. Smith ◽  
Satomi Maekawa ◽  
...  
Keyword(s):  
Repeat Expansion ◽  
C9orf72 Repeat Expansion
Sign in / Sign up

Export Citation Format

Share Document