Poly-GR dipeptide repeat polymers correlate with neurodegeneration and Clinicopathological subtypes in C9ORF72-related brain disease
Abstract Frontotemporal lobar degeneration (FTLD) is heterogeneous in clinical presentation, neuropathological characteristics and genetics. An expanded GGGGCC hexanucleotide repeat in C9ORF72 is the most common genetic cause of both FTLD and motor neuron disease (MND). Dipeptide repeat polymers (DP...
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| Format: | Article |
| Language: | English |
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BMC
2018-07-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-018-0564-7 |
| _version_ | 1818007894997598208 |
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| author | Nobutaka Sakae Kevin F. Bieniek Yong-Jie Zhang Kelly Ross Tania F. Gendron Melissa E. Murray Rosa Rademakers Leonard Petrucelli Dennis W. Dickson |
| author_facet | Nobutaka Sakae Kevin F. Bieniek Yong-Jie Zhang Kelly Ross Tania F. Gendron Melissa E. Murray Rosa Rademakers Leonard Petrucelli Dennis W. Dickson |
| author_sort | Nobutaka Sakae |
| collection | DOAJ |
| description | Abstract Frontotemporal lobar degeneration (FTLD) is heterogeneous in clinical presentation, neuropathological characteristics and genetics. An expanded GGGGCC hexanucleotide repeat in C9ORF72 is the most common genetic cause of both FTLD and motor neuron disease (MND). Dipeptide repeat polymers (DPR) are generated through repeat-associated non-ATG translation, and they aggregate in neuronal inclusions with a distribution distinct from that of TDP-43 pathology. Recent studies from animal and cell culture models suggest that DPR might be toxic, but that toxicity may differ for specific DPR. Arginine containing DPR (poly-GR and poly-PR) have the greatest toxicity and are less frequent than other DPR (poly-GP, poly-GA). A unique feature of arginine-containing DPR is their potential for post-translational modification by methyl-transferases, which produces methylarginine DPR. In this report, we explored the relationship of DPR and methylarginine to markers of neurodegeneration using quantitative digital microscopic methods in 40 patients with C9ORF72 mutations and one of three different clinicopathologic phenotypes, FTLD, FTLD-MND or MND. We find that density and distribution of poly-GR inclusions are different from poly-GA and poly-GP inclusions. We also demonstrate colocalization of poly-GR with asymmetrical dimethylarginine (aDMA) immunoreactivity in regions with neurodegeneration. Differences in aDMA were also noted by clinical phenotype. FTLD-MND had the highest burden of poly-GR pathology compared to FTLD and MND, while FTLD-MND had higher burden of aDMA than FTLD. The results suggest that poly-GR pathology is associated with toxicity and neurodegeneration. It remains to be determined if dimethylarginine modification of poly-GR could contribute to its toxicity. |
| first_indexed | 2024-04-14T05:21:52Z |
| format | Article |
| id | doaj.art-b4d3f85f432446c0843f7b0eb2a3a620 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-04-14T05:21:52Z |
| publishDate | 2018-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-b4d3f85f432446c0843f7b0eb2a3a6202022-12-22T02:10:10ZengBMCActa Neuropathologica Communications2051-59602018-07-016111310.1186/s40478-018-0564-7Poly-GR dipeptide repeat polymers correlate with neurodegeneration and Clinicopathological subtypes in C9ORF72-related brain diseaseNobutaka Sakae0Kevin F. Bieniek1Yong-Jie Zhang2Kelly Ross3Tania F. Gendron4Melissa E. Murray5Rosa Rademakers6Leonard Petrucelli7Dennis W. Dickson8Department of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicAbstract Frontotemporal lobar degeneration (FTLD) is heterogeneous in clinical presentation, neuropathological characteristics and genetics. An expanded GGGGCC hexanucleotide repeat in C9ORF72 is the most common genetic cause of both FTLD and motor neuron disease (MND). Dipeptide repeat polymers (DPR) are generated through repeat-associated non-ATG translation, and they aggregate in neuronal inclusions with a distribution distinct from that of TDP-43 pathology. Recent studies from animal and cell culture models suggest that DPR might be toxic, but that toxicity may differ for specific DPR. Arginine containing DPR (poly-GR and poly-PR) have the greatest toxicity and are less frequent than other DPR (poly-GP, poly-GA). A unique feature of arginine-containing DPR is their potential for post-translational modification by methyl-transferases, which produces methylarginine DPR. In this report, we explored the relationship of DPR and methylarginine to markers of neurodegeneration using quantitative digital microscopic methods in 40 patients with C9ORF72 mutations and one of three different clinicopathologic phenotypes, FTLD, FTLD-MND or MND. We find that density and distribution of poly-GR inclusions are different from poly-GA and poly-GP inclusions. We also demonstrate colocalization of poly-GR with asymmetrical dimethylarginine (aDMA) immunoreactivity in regions with neurodegeneration. Differences in aDMA were also noted by clinical phenotype. FTLD-MND had the highest burden of poly-GR pathology compared to FTLD and MND, while FTLD-MND had higher burden of aDMA than FTLD. The results suggest that poly-GR pathology is associated with toxicity and neurodegeneration. It remains to be determined if dimethylarginine modification of poly-GR could contribute to its toxicity.http://link.springer.com/article/10.1186/s40478-018-0564-7C9ORF72Dipeptide repeat polymers (DPR)Poly-GRNeurodegenerationDimethylarginine |
| spellingShingle | Nobutaka Sakae Kevin F. Bieniek Yong-Jie Zhang Kelly Ross Tania F. Gendron Melissa E. Murray Rosa Rademakers Leonard Petrucelli Dennis W. Dickson Poly-GR dipeptide repeat polymers correlate with neurodegeneration and Clinicopathological subtypes in C9ORF72-related brain disease Acta Neuropathologica Communications C9ORF72 Dipeptide repeat polymers (DPR) Poly-GR Neurodegeneration Dimethylarginine |
| title | Poly-GR dipeptide repeat polymers correlate with neurodegeneration and Clinicopathological subtypes in C9ORF72-related brain disease |
| title_full | Poly-GR dipeptide repeat polymers correlate with neurodegeneration and Clinicopathological subtypes in C9ORF72-related brain disease |
| title_fullStr | Poly-GR dipeptide repeat polymers correlate with neurodegeneration and Clinicopathological subtypes in C9ORF72-related brain disease |
| title_full_unstemmed | Poly-GR dipeptide repeat polymers correlate with neurodegeneration and Clinicopathological subtypes in C9ORF72-related brain disease |
| title_short | Poly-GR dipeptide repeat polymers correlate with neurodegeneration and Clinicopathological subtypes in C9ORF72-related brain disease |
| title_sort | poly gr dipeptide repeat polymers correlate with neurodegeneration and clinicopathological subtypes in c9orf72 related brain disease |
| topic | C9ORF72 Dipeptide repeat polymers (DPR) Poly-GR Neurodegeneration Dimethylarginine |
| url | http://link.springer.com/article/10.1186/s40478-018-0564-7 |
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