C9orf72 immunohistochemistry in Alzheimer's disease
Alzheimer's Research & Therapy volume 4, Article number: 37 (2012)
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.
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 . C9orf72 repeat expansion mutation in large cohorts of patients with AD has been either absent  or identified exceedingly rarely .
In the previous issue of Alzheimer's Research & Therapy, Satoh and colleagues  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 ). 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  in comparison with Caucasian patients . 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.
amyotrophic lateral sclerosis
frontotemporal dementia or amyotrophic lateral sclerosis (or both) linked to chromosome 9
chromosome 9 open reading frame 72
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 ALS. Neuron. 2011, 72: 245-256. 10.1016/j.neuron.2011.09.011.
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-FTD. Neuron. 2011, 72: 257-268. 10.1016/j.neuron.2011.09.010.
Schymick JC, Traynor BJ: Expanding the genetics of amyotrophic lateral sclerosis and frontotemporal dementia. Alzheimers Res Ther. 2012, 4: 30-10.1186/alzrt133.
Al-Chalabi A, Jones A, Troakes C, King A, Al-Sarraj S, van den Berg LH: The genetics and neuropathology of amyotrophic lateral sclerosis. Acta Neuropathol. 2012, 124: 339-352. 10.1007/s00401-012-1022-4.
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 degeneration. Acta Neuropathol. 2012, 124: 353-372. 10.1007/s00401-012-1029-x.
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/ALS. Acta Neuropathol. 2011, 122: 691-702. 10.1007/s00401-011-0911-2.
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 C9ORF72. Acta Neuropathol. 2011, 122: 673-690. 10.1007/s00401-011-0907-y.
Boeve BF, Graff-Radford NR: Cognitive and behavioral features of c9FTD/ALS. Alzheimers Res Ther. 2012, 4: 29-10.1186/alzrt132.
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 decline. Neuropathology. 2011,
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 expansion. Acta Neuropathol. 2012, 123: 825-839. 10.1007/s00401-012-0970-z.
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 disease. Neurobiol Aging. 2012, 33: 1846 e5-6.
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 disease. N Engl J Med. 2012, 366: 283-284. 10.1056/NEJMc1113592.
Satoh JI, Tabunoki H, Ishida T, Saito Y, Arima K: Dystrophic neurites express C9orf72 in Alzheimer's disease brains. Alzheimers Res Ther. 2012, 4: 33-10.1186/alzrt136.
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 sclerosis. Neurobiol Aging. 2012, 33: 2527. e11-6.
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 founder. Eur J Hum Genet. 2012,
The author declares that they have no competing interests.
About this article
Cite this article
Hortobágyi, T. C9orf72 immunohistochemistry in Alzheimer's disease. Alz Res Therapy 4, 37 (2012). https://doi.org/10.1186/alzrt140
- Amyotrophic Lateral Sclerosis
- Multiple System Atrophy
- Frontotemporal Dementia
- Dystrophic Neurites
- Sporadic Amyotrophic Lateral Sclerosis