Document Detail

C9orf72 immunohistochemistry in Alzheimer's disease.
Jump to Full Text
MedLine Citation:
PMID:  23014271     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Mutation in chromosome 9 open reading frame 72 (C9orf72) is a major genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), referred to as C9FTD/ALS. The function of the protein is currently unknown, and the pathomechanism of C9FTD/ALS remains to be elucidated. The study by Satoh and colleagues in the previous issue of Alzheimer's Research & Therapy presents important new findings on C9orf72 protein expression in neurodegenerative disorders along with characterization of C9orf72 antibodies.
Tibor Hortobágyi
Publication Detail:
Type:  Journal Article     Date:  2012-09-26
Journal Detail:
Title:  Alzheimer's research & therapy     Volume:  4     ISSN:  1758-9193     ISO Abbreviation:  Alzheimers Res Ther     Publication Date:  2012  
Date Detail:
Created Date:  2014-05-20     Completed Date:  2014-05-20     Revised Date:  2014-05-20    
Medline Journal Info:
Nlm Unique ID:  101511643     Medline TA:  Alzheimers Res Ther     Country:  England    
Other Details:
Languages:  eng     Pagination:  37     Citation Subset:  -    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Alzheimers Res Ther
Journal ID (iso-abbrev): Alzheimers Res Ther
ISSN: 1758-9193
Publisher: BioMed Central
Article Information
Download PDF
Copyright ©2012 BioMed Central Ltd
collection publication date: Year: 2012
Electronic publication date: Day: 26 Month: 9 Year: 2012
pmc-release publication date: Day: 26 Month: 3 Year: 2013
Volume: 4 Issue: 5
First Page: 37 Last Page: 37
PubMed Id: 23014271
ID: 3580394
Publisher Id: alzrt140
DOI: 10.1186/alzrt140

C9orf72 immunohistochemistry in Alzheimer's disease
Tibor Hortobágyi12 Email:
1Department of Neuropathology, Institute of Pathology, Medical and Health Science Centre, University of Debrecen, 4032 Debrecen, Nagyerdei krt. 98., Hungary
2Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, De Crespigny Park, London, SE5 8AF, UK

Chromosome 9 open reading frame 72 (C9orf72) is a protein with unknown function and a high level of expression in the brain and spinal cord. The discovery of expanded heptanucleotide repeat mutations as the most common genetic cause of familial and sporadic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) [1,2] provided further evidence for a phenotypic spectrum with overlapping genetic [3-5], pathological [6,7], and clinical [8,9] features. C9orf72 mutant FTD and ALS (C9FTD/ALS) cases reveal a characteristic neuropathological signature with abundant p62-positive inclusions in the hippocampus and cerebellum [6,7] and a unique pattern of ubiquilin pathology [10]. C9orf72 repeat expansion mutation in large cohorts of patients with AD has been either absent [11] or identified exceedingly rarely [12].

In the previous issue of Alzheimer's Research & Therapy, Satoh and colleagues [13] present an analysis of C9orf72 expression and its relation to ubiquitin, p62, and ubiquilin-1, ubiquilin-2 immunoreactivity in control, Alzheimer's disease (AD), sporadic ALS, Parkinson's disease, and multiple system atrophy brains. Early studies have consistently shown that C9orf72 is negative in intracellular inclusions including tau-positive structures except for Pick bodies (for references, see [13]). In contrast to these previous studies, Satoh and colleagues report C9orf72 in a subset of dystrophic neurites in AD. Another major finding is the demonstration of C9orf72 and ubiquilin-1 positivity in a cluster of dystrophic neurites in senile plaques in AD brains by using antibodies discriminating ubiquilin-1 from ubiquilin-2; these results warrant further studies into the role of ubiquilin in neurodegeneration. The thorough analysis of two different anti-C9orf72 antibodies for the pattern of immunoreactivity, specificity, cross-reactivities is an important aspect of the study. The results suggest that the testing of further antibodies available on the market and the generation of novel highly specific anti-C9orf72 antibodies are necessary to facilitate research into neurodegenerative diseases, in particular C9FTD/ALS. Unfortunately, C9orf72 mutation status has not been analyzed in the included cases either; Satoh and colleagues assume that cases are likely to be negative in view of the low prevalence of C9orf72 mutation in ALS and FTD in Japanese patients [14] in comparison with Caucasian patients [15]. Pathological proteins incorporated into characteristic inclusions in neurodegenerative diseases are rather detergent-insoluble; the analysis of this key feature is still awaited. The case numbers are low in this study. Therefore, as the authors themselves have suggested, further studies are needed to test the presented findings in larger cohorts and by more detailed analysis. This paper provides a nidus around which the presented observations can be more robustly studied and clarified.


AD: Alzheimer's disease; ALS: amyotrophic lateral sclerosis; C9FTD/ALS: frontotemporal dementia or amyotrophic lateral sclerosis (or both) linked to chromosome 9; C9orf72: chromosome 9 open reading frame 72; FTD: frontotemporal dementia.

Competing interests

The author declares that they have no competing interests.

DeJesus-Hernandez M,Mackenzie IR,Boeve BF,Boxer AL,Baker M,Rutherford NJ,Nicholson AM,Finch NA,Flynn H,Adamson J,Kouri N,Wojtas A,Sengdy P,Hsiung GY,Karydas A,Seeley WW,Josephs KA,Coppola G,Geschwind DH,Wszolek ZK,Feldman H,Knopman DS,Petersen RC,Miller BL,Dickson DW,Boylan KB,Graff-Radford NR,Rademakers R,Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALSNeuronYear: 20117224525610.1016/j.neuron.2011.09.01121944778
Renton AE,Majounie E,Waite A,Simón-Sánchez J,Rollinson S,Gibbs JR,Schymick JC,Laaksovirta H,van Swieten JC,Myllykangas L,Kalimo H,Paetau A,Abramzon Y,Remes AM,Kaganovich A,Scholz SW,Duckworth J,Ding J,Harmer DW,Hernandez DG,Johnson JO,Mok K,Ryten M,Trabzuni D,Guerreiro RJ,Orrell RW,Neal J,Murray A,Pearson J,Jansen IE,et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTDNeuronYear: 20117225726810.1016/j.neuron.2011.09.01021944779
Schymick JC,Traynor BJ,Expanding the genetics of amyotrophic lateral sclerosis and frontotemporal dementiaAlzheimers Res TherYear: 201243010.1186/alzrt13322835154
Al-Chalabi A,Jones A,Troakes C,King A,Al-Sarraj S,van den Berg LH,The genetics and neuropathology of amyotrophic lateral sclerosisActa NeuropatholYear: 201212433935210.1007/s00401-012-1022-422903397
Sieben A,Van Langenhove T,Engelborghs S,Martin JJ,Boon P,Cras P,De Deyn PP,Santens P,Van Broeckhoven C,Cruts M,The genetics and neuropathology of frontotemporal lobar degenerationActa NeuropatholYear: 201212435337210.1007/s00401-012-1029-x22890575
Al-Sarraj S,King A,Troakes C,Smith B,Maekawa S,Bodi I,Rogelj B,Al-Chalabi A,Hortobágyi T,Shaw CE,p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALSActa NeuropatholYear: 201112269170210.1007/s00401-011-0911-222101323
Murray ME,DeJesus-Hernandez M,Rutherford NJ,Baker M,Duara R,Graff-Radford NR,Wszolek ZK,Ferman TJ,Josephs KA,Boylan KB,Rademakers R,Dickson DW,Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72Acta NeuropatholYear: 201112267369010.1007/s00401-011-0907-y22083254
Boeve BF,Graff-Radford NR,Cognitive and behavioral features of c9FTD/ALSAlzheimers Res TherYear: 201242910.1186/alzrt13222817642
Troakes C,Maekawa S,Wijesekera L,Rogelj B,Siklós L,Bell C,Smith B,Newhouse S,Vance C,Johnson L,Hortobágyi T,Shatunov A,Al-Chalabi A,Leigh N,Shaw CE,King A,Al-Sarraj S,An MND/ALS phenotype associated with C9orf72 repeat expansion: Abundant p62-positive, TDP-43-negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive declineNeuropathologyYear: 2011 in press .
Brettschneider J,Van Deerlin VM,Robinson JL,Kwong L,Lee EB,Ali YO,Safren N,Monteiro MJ,Toledo JB,Elman L,McCluskey L,Irwin DJ,Grossman M,Molina-Porcel L,Lee VM,Trojanowski JQ,Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansionActa NeuropatholYear: 201212382583910.1007/s00401-012-0970-z22426854
Rollinson S,Halliwell N,Young K,Callister JB,Toulson G,Gibbons L,Davidson YS,Robinson AC,Gerhard A,Richardson A,Neary D,Snowden J,Mann DM,Pickering-Brown SM,Analysis of the hexanucleotide repeat in C9ORF72 in Alzheimer's diseaseNeurobiol AgingYear: 2012331846 e5622410647
Majounie E,Abramzon Y,Renton AE,Perry R,Bassett SS,Pletnikova O,Troncoso JC,Hardy J,Singleton AB,Traynor BJ,Repeat expansion in C9ORF72 in Alzheimer's diseaseN Engl J MedYear: 201236628328410.1056/NEJMc111359222216764
Satoh JI,Tabunoki H,Ishida T,Saito Y,Arima K,Dystrophic neurites express C9orf72 in Alzheimer's disease brainsAlzheimers Res TherYear: 201243310.1186/alzrt13622898310
Ogaki K,Li Y,Atsuta N,Tomiyama H,Funayama M,Watanabe H,Nakamura R,Yoshino H,Yato S,Tamura A,Naito Y,Taniguchi A,Fujita K,Izumi Y,Kaji R,Hattori N,Sobue G,Japanese Consortium for Amyotrophic Lateral Sclerosis research (JaCALS)Analysis of C9orf72 repeat expansion in 563 Japanese patients with amyotrophic lateral sclerosisNeurobiol AgingYear: 2012332527. e11622727276
Smith BN,Newhouse S,Shatunov A,Vance C,Topp S,Johnson L,Miller J,Lee Y,Troakes C,Scott KM,Jones A,Gray I,Wright J,Hortobágyi T,Al-Sarraj S,Rogelj B,Powell J,Lupton M,Lovestone S,Sapp PC,Weber M,Nestor PJ,Schelhaas HJ,Asbroek AA,Silani V,Gellera C,Taroni F,Ticozzi N,Van den Berg L,Veldink J,et al. The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founderEur J Hum GenetYear: 2012 in press .

Article Categories:
  • Commentary

Previous Document:  Different ophthalmologic manifestations of sarcoidosis.
Next Document:  The [Formula: see text] insulator Sr(3)Ir(2)O(7) studied by means of angle-resolved photoemission sp...