Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Acta Neuropathologica
Published in: Acta Neuropathologica 3/2013

01-03-2013 | Original Paper

hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations

Authors: Kohji Mori, Sven Lammich, Ian R. A. Mackenzie, Ignasi Forné, Sonja Zilow, Hans Kretzschmar, Dieter Edbauer, Jonathan Janssens, Gernot Kleinberger, Marc Cruts, Jochen Herms, Manuela Neumann, Christine Van Broeckhoven, Thomas Arzberger, Christian Haass

Published in: Acta Neuropathologica | Issue 3/2013

Login to get access

Abstract

Genetic analysis revealed the hexanucleotide repeat expansion GGGGCC within the regulatory region of the gene C9orf72 as the most common cause of familial amyotrophic lateral sclerosis and the second most common cause of frontotemporal lobar degeneration. Since repeat expansions might cause RNA toxicity via sequestration of RNA-binding proteins, we searched for proteins capable of binding to GGGGCC repeats. In vitro-transcribed biotinylated RNA containing hexanucleotide GGGGCC or, as control, AAAACC repeats were incubated with nuclear protein extracts. Using stringent filtering protocols 20 RNA-binding proteins with a variety of different functions in RNA metabolism, translation and transport were identified. A subset of these proteins was further investigated by immunohistochemistry in human autopsy brains. This revealed that hnRNP A3 formed neuronal cytoplasmic and intranuclear inclusions in the hippocampus of patients with C9orf72 repeat extensions. Confocal microcopy showed that these inclusions belong to the group of the so far enigmatic p62-positive/TDP-43 negative inclusions characteristically seen in autopsy cases of diseased C9orf72 repeat expansion carriers. Thus, we have identified one protein component of these pathognomonic inclusions.
Appendix
Available only for authorised users
Literature
1.
Al-Sarraj S, King A, Troakes C et al (2011) 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 122(6):691–702PubMedCrossRef
2.
Arai T, Hasegawa M, Akiyama H et al (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351(3):602–611PubMedCrossRef
3.
Baker M, Mackenzie IR, Pickering-Brown SM et al (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442(7105):916–919PubMedCrossRef
4.
Benajiba L, Le Ber I, Camuzat A et al (2009) TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration. Ann Neurol 65(4):470–473PubMedCrossRef
5.
Brettschneider J, Van Deerlin VM, Robinson JL et al (2012) Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion. Acta Neuropathol 123(6):825–839PubMedCrossRef
6.
Collins M, Riascos D, Kovalik T et al (2012) The RNA-binding motif 45 (RBM45) protein accumulates in inclusion bodies in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) patients. Acta Neuropathol 124(5):717–732PubMedCrossRef
7.
Cruts M, Gijselinck I, van der Zee J et al (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442(7105):920–924PubMedCrossRef
8.
DeJesus-Hernandez M, Mackenzie IR, Boeve BF et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72(2):245–256PubMedCrossRef
9.
Dignam JD, Lebovitz RM, Roeder RG (1983) Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res 11(5):1475–1489PubMedCrossRef
10.
Dormann D, Madl T, Valori CF et al (2012) Arginine methylation next to the PY-NLS modulates transportin binding and nuclear import of FUS. EMBO J 31(22):4258–4275PubMedCrossRef
11.
Elden AC, Kim HJ, Hart MP et al (2010) Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466(7310):1069–1075PubMedCrossRef
12.
Fratta P, Mizielinska S, Nicoll AJ et al (2012) C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci Rep 2:1016PubMedCrossRef
13.
14.
Gijselinck I, Van Langenhove T, van der Zee J et al (2012) A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol 11(1):54–65PubMedCrossRef
15.
16.
Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8(2):101–112PubMedCrossRef
17.
He Y, Smith R (2009) Nuclear functions of heterogeneous nuclear ribonucleoproteins A/B. Cell Mol Life Sci 66(7):1239–1256PubMedCrossRef
18.
Hilleren PJ, Parker R (2003) Cytoplasmic degradation of splice-defective pre-mRNAs and intermediates. Mol Cell 12(6):1453–1465PubMedCrossRef
19.
Keller BA, Volkening K, Droppelmann CA et al (2012) Co-aggregation of RNA binding proteins in ALS spinal motor neurons: evidence of a common pathogenic mechanism. Acta Neuropathol 124(5):733–747PubMedCrossRef
20.
Kwiatkowski TJ Jr, Bosco DA, Leclerc AL et al (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323(5918):1205–1208PubMedCrossRef
21.
Ma AS, Moran-Jones K, Shan J et al (2002) Heterogeneous nuclear ribonucleoprotein A3, a novel RNA trafficking response element-binding protein. J Biol Chem 277(20):18010–18020PubMedCrossRef
22.
Mackenzie IR, Neumann M, Baborie A et al (2011) A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 122(1):111–113PubMedCrossRef
23.
Maruyama H, Morino H, Ito H et al (2010) Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465(7295):223–226PubMedCrossRef
24.
Neumann M, Kwong LK, Lee EB et al (2009) Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. Acta Neuropathol 117(2):137–149PubMedCrossRef
25.
Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314(5796):130–133PubMedCrossRef
26.
Papadopoulou C, Boukakis G, Ganou V et al (2012) Expression profile and interactions of hnRNP A3 within hnRNP/mRNP complexes in mammals. Arch Biochem Biophys 523(2):151–160PubMedCrossRef
27.
Rademakers R, Neumann M, Mackenzie IR (2012) Advances in understanding the molecular basis of frontotemporal dementia. Nat Rev Neurol 8(8):423–434PubMed
28.
29.
Renton AE, Majounie E, Waite A et al (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72(2):257–268PubMedCrossRef
30.
Rosen DR, Siddique T, Patterson D et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362(6415):59–62PubMedCrossRef
31.
Schreiner B, Westerburg H, Forne I et al (2012) Role of the AAA protease Yme1 in folding of proteins in the intermembrane space of mitochondria. Mol Biol Cell doi. doi:10.​1091/​mbc.​E12-05-0420
32.
Shevchenko A, Chernushevich I, Wilm M, Mann M (2000) De Novo peptide sequencing by nanoelectrospray tandem mass spectrometry using triple quadrupole and quadrupole/time-of-flight instruments. Methods Mol Biol 146:1–16PubMed
33.
Sieben A, Van Langenhove T, Engelborghs S et al (2012) The genetics and neuropathology of frontotemporal lobar degeneration. Acta Neuropathol 124(3):353–372PubMedCrossRef
34.
Simon-Sanchez J, Dopper EG, Cohn-Hokke PE et al (2012) The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions. Brain 135(Pt 3):723–735PubMedCrossRef
35.
Skibinski G, Parkinson NJ, Brown JM et al (2005) Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat Genet 37(8):806–808PubMedCrossRef
36.
Sreedharan J, Blair IP, Tripathi VB et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319(5870):1668–1672PubMedCrossRef
37.
Thompson DM, Parker R (2007) Cytoplasmic decay of intergenic transcripts in Saccharomyces cerevisiae. Mol Cell Biol 27(1):92–101PubMedCrossRef
38.
Van Deerlin VM, Sleiman PM, Martinez-Lage M et al (2010) Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet 42(3):234–239PubMedCrossRef
39.
van der Zee J, Gijselinck I, Dillen L et al (2012) A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence. Genomic Instability and intermediate repeats. Hum Mutat. doi:10.​1002/​humu.​22244
40.
Vance C, Rogelj B, Hortobagyi T et al (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323(5918):1208–1211PubMedCrossRef
41.
Watts GD, Wymer J, Kovach MJ et al (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36(4):377–381PubMedCrossRef
42.
Wilm M, Shevchenko A, Houthaeve T et al (1996) Femtomole sequencing of proteins from polyacrylamide gels by nano-electrospray mass spectrometry. Nature 379(6564):466–469PubMedCrossRef
43.
Wu CH, Fallini C, Ticozzi N et al (2012) Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488(7412):499–503PubMedCrossRef
44.
Zu T, Gibbens B, Doty NS et al (2011) Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci USA 108(1):260–265PubMedCrossRef
Metadata
Title
hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations
Authors
Kohji Mori
Sven Lammich
Ian R. A. Mackenzie
Ignasi Forné
Sonja Zilow
Hans Kretzschmar
Dieter Edbauer
Jonathan Janssens
Gernot Kleinberger
Marc Cruts
Jochen Herms
Manuela Neumann
Christine Van Broeckhoven
Thomas Arzberger
Christian Haass
Publication date
01-03-2013
Publisher
Springer-Verlag
Published in
Acta Neuropathologica / Issue 3/2013
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-013-1088-7

Other articles of this Issue 3/2013

Acta Neuropathologica 3/2013 Go to the issue

Original Paper

Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations

Original Paper

Sequence variants in eukaryotic translation initiation factor 4-gamma (eIF4G1) are associated with Lewy body dementia

Erratum

Erratum to: APP mutations in the Aβ coding region are associated with abundant cerebral deposition of Aβ38

Original Paper

OTX2 sustains a bivalent-like state of OTX2-bound promoters in medulloblastoma by maintaining their H3K27me3 levels

Correspondence

Lysosomal storage and advanced senescence in the brain of LAMP-2-deficient Danon disease

Original Paper

VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy