Antisense RNA foci are associated with nucleoli and TDP-43 mislocalization in C9orf72-ALS/FTD: a quantitative study

doi:10.1007/s00401-018-01955-0

. 2019 Mar;137(3):527-530.

doi: 10.1007/s00401-018-01955-0. Epub 2019 Jan 21.

Antisense RNA foci are associated with nucleoli and TDP-43 mislocalization in C9orf72-ALS/FTD: a quantitative study

Olubankole Aladesuyi Arogundade¹, Jennifer E Stauffer^{1

2}, Shahram Saberi^{1

3}, Sandra Diaz-Garcia¹, Sahana Malik^{1

4}, Hani Basilim^{1

5}, Maria J Rodriguez¹, Takuya Ohkubo¹, John Ravits⁶

Affiliations

¹ Department of Neuroscience, University of California, San Diego, 9500 Gilman Drive, MS-0624, La Jolla, CA, 92093, USA.
² The Jackson Laboratory, 600 Main St, Bar Harbor, ME, 04609, USA.
³ Department of Pathology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1194, New York, NY, 10029, USA.
⁴ Cooper Medical School of Rowan University, 401 South Broadway, Camden, NJ, 08103, USA.
⁵ King Abdullah Medical Complex Jeddah (KAMCJ), Ameer Naif Road, Al-Shera'a, Jidda, 23816, Saudi Arabia.
⁶ Department of Neuroscience, University of California, San Diego, 9500 Gilman Drive, MS-0624, La Jolla, CA, 92093, USA. jravits@ucsd.edu.

PMID: 30666413
PMCID: PMC6397670
DOI: 10.1007/s00401-018-01955-0

Antisense RNA foci are associated with nucleoli and TDP-43 mislocalization in C9orf72-ALS/FTD: a quantitative study

Olubankole Aladesuyi Arogundade et al. Acta Neuropathol. 2019 Mar.

. 2019 Mar;137(3):527-530.

doi: 10.1007/s00401-018-01955-0. Epub 2019 Jan 21.

Authors

Affiliations

¹ Department of Neuroscience, University of California, San Diego, 9500 Gilman Drive, MS-0624, La Jolla, CA, 92093, USA.
² The Jackson Laboratory, 600 Main St, Bar Harbor, ME, 04609, USA.
³ Department of Pathology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1194, New York, NY, 10029, USA.
⁴ Cooper Medical School of Rowan University, 401 South Broadway, Camden, NJ, 08103, USA.
⁵ King Abdullah Medical Complex Jeddah (KAMCJ), Ameer Naif Road, Al-Shera'a, Jidda, 23816, Saudi Arabia.
⁶ Department of Neuroscience, University of California, San Diego, 9500 Gilman Drive, MS-0624, La Jolla, CA, 92093, USA. jravits@ucsd.edu.

PMID: 30666413
PMCID: PMC6397670
DOI: 10.1007/s00401-018-01955-0

No abstract available

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Conflict of interest statement

Conflict of Interest

The authors declare that they have no conflict of interest.

Figures

**Fig. 1. Antisense RNA foci have unique neuropathological features compared to sense RNA foci.**
(a): Sense and antisense RNA foci (arrowheads) are observed in the nucleoplasm or on the periphery of nucleoli of neurons (outer, middle and innermost dashed lines mark the cytoplasm, nucleoplasm and nucleolus, respectively). (b): Nucleolar localization is confirmed by nucleolar marker nucleolin. (c and d): Neurons containing antisense RNA foci often have cytoplasmic aggregation of TDP-43 and neurons with sense RNA foci often have preserved nuclear TDP-43 (inset scale, 500 nm). (e): The percentage of neurons with nucleolar antisense RNA foci was significantly increased in neurons with cytoplasmic aggregation of TDP-43 compared to preserved nuclear TDP-43 (p = 0.008). (f): The percentage of neurons with nucleolar sense RNA foci was not significantly different in neurons with cytoplasmic aggregation of TDP-43 compared to preserved nuclear TDP-43 (p = 0.7, MannWhitney test). (g): The co-occurrence of nucleolar antisense RNA foci and cytoplasmic aggregation of TDP-43 is significantly greater than expected while the co-occurrence of nucleolar sense RNA foci and cytoplasmic aggregation of TDP-43 is not. Area proportional Venn-diagrams represent Fisher’s exact test. Data is from motor neurons within the anterior horn of spinal cord.

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References

1. Cooper-Knock J, Higginbottom A, Stopford MJ, Highley JR, Ince PG, Wharton SB, et al. (2015) Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy. Acta Neuropathol 130:63–75. doi: 10.1007/s00401-015-1429-9. - DOI - PMC - PubMed
1. Cooper-Knock J, Walsh MJ, Higginbottom A, Highley JR, Dickman MJ, Edbauer D, et al. (2014) Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain 137:2040–2051. doi: 10.1093/brain/awu120. - DOI - PMC - PubMed
1. DeJesus-Hernandez M, Finch NCA, Wang X, Gendron TF, Bieniek KF, Heckman MG, et al. (2017) In-depth clinico-pathological examination of RNA foci in a large cohort of C9ORF72 expansion carriers. Acta Neuropathol 134(2):255–269. doi: 10.1007/s00401-017-1725-7. - DOI - PMC - PubMed
1. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. (2011) Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS. Neuron 72(2):245–56. doi: 10.1016/j.neuron.2011.09.011. - DOI - PMC - PubMed
1. Gendron TF, Bieniek KF, Zhang YJ, Jansen-West K, Ash PEA, Caulfield T, et al. (2013) Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS. Acta Neuropathol 126:829–844. doi: 10.1007/s00401-013-1192-8. - DOI - PMC - PubMed

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[1] Cooper-Knock J, Higginbottom A, Stopford MJ, Highley JR, Ince PG, Wharton SB, et al. (2015) Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy. Acta Neuropathol 130:63–75. doi: 10.1007/s00401-015-1429-9. - DOI - PMC - PubMed

[2] Cooper-Knock J, Higginbottom A, Stopford MJ, Highley JR, Ince PG, Wharton SB, et al. (2015) Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy. Acta Neuropathol 130:63–75. doi: 10.1007/s00401-015-1429-9. - DOI - PMC - PubMed

[3] Cooper-Knock J, Walsh MJ, Higginbottom A, Highley JR, Dickman MJ, Edbauer D, et al. (2014) Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain 137:2040–2051. doi: 10.1093/brain/awu120. - DOI - PMC - PubMed

[4] Cooper-Knock J, Walsh MJ, Higginbottom A, Highley JR, Dickman MJ, Edbauer D, et al. (2014) Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain 137:2040–2051. doi: 10.1093/brain/awu120. - DOI - PMC - PubMed

[5] DeJesus-Hernandez M, Finch NCA, Wang X, Gendron TF, Bieniek KF, Heckman MG, et al. (2017) In-depth clinico-pathological examination of RNA foci in a large cohort of C9ORF72 expansion carriers. Acta Neuropathol 134(2):255–269. doi: 10.1007/s00401-017-1725-7. - DOI - PMC - PubMed

[6] DeJesus-Hernandez M, Finch NCA, Wang X, Gendron TF, Bieniek KF, Heckman MG, et al. (2017) In-depth clinico-pathological examination of RNA foci in a large cohort of C9ORF72 expansion carriers. Acta Neuropathol 134(2):255–269. doi: 10.1007/s00401-017-1725-7. - DOI - PMC - PubMed

[7] DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. (2011) Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS. Neuron 72(2):245–56. doi: 10.1016/j.neuron.2011.09.011. - DOI - PMC - PubMed

[8] DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. (2011) Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS. Neuron 72(2):245–56. doi: 10.1016/j.neuron.2011.09.011. - DOI - PMC - PubMed

[9] Gendron TF, Bieniek KF, Zhang YJ, Jansen-West K, Ash PEA, Caulfield T, et al. (2013) Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS. Acta Neuropathol 126:829–844. doi: 10.1007/s00401-013-1192-8. - DOI - PMC - PubMed

[10] Gendron TF, Bieniek KF, Zhang YJ, Jansen-West K, Ash PEA, Caulfield T, et al. (2013) Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS. Acta Neuropathol 126:829–844. doi: 10.1007/s00401-013-1192-8. - DOI - PMC - PubMed

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Antisense RNA foci are associated with nucleoli and TDP-43 mislocalization in C9orf72-ALS/FTD: a quantitative study

Affiliations

Antisense RNA foci are associated with nucleoli and TDP-43 mislocalization in C9orf72-ALS/FTD: a quantitative study

Authors

Affiliations

Conflict of interest statement

Figures

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Cited by

References

Publication types

MeSH terms

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Supplementary concepts

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LinkOut - more resources

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Medical

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