A novel MAPT mutation, G55R, in a frontotemporal dementia patient leads to altered Tau function.
Over two dozen mutations in the gene encoding the microtubule associated protein tau cause a variety of neurodegenerative dementias known as tauopathies, including frontotemporal dementia (FTD), PSP, CBD and Pick's disease. The vast majority of these mutations map to the C-terminal region of ta...
Guardado en:
| Autores principales: | , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2013
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/f20d01dc6d6a4752b89ec843954ba1dc |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:f20d01dc6d6a4752b89ec843954ba1dc |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:f20d01dc6d6a4752b89ec843954ba1dc2021-11-18T08:53:32ZA novel MAPT mutation, G55R, in a frontotemporal dementia patient leads to altered Tau function.1932-620310.1371/journal.pone.0076409https://doaj.org/article/f20d01dc6d6a4752b89ec843954ba1dc2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24086739/?tool=EBIhttps://doaj.org/toc/1932-6203Over two dozen mutations in the gene encoding the microtubule associated protein tau cause a variety of neurodegenerative dementias known as tauopathies, including frontotemporal dementia (FTD), PSP, CBD and Pick's disease. The vast majority of these mutations map to the C-terminal region of tau possessing microtubule assembly and microtubule dynamics regulatory activities as well as the ability to promote pathological tau aggregation. Here, we describe a novel and non-conservative tau mutation (G55R) mapping to an alternatively spliced exon encoding part of the N-terminal region of the protein in a patient with the behavioral variant of FTD. Although less well understood than the C-terminal region of tau, the N-terminal region can influence both MT mediated effects as well as tau aggregation. The mutation changes an uncharged glycine to a basic arginine in the midst of a highly conserved and very acidic region. In vitro, 4-repeat G55R tau nucleates microtubule assembly more effectively than wild-type 4-repeat tau; surprisingly, this effect is tau isoform specific and is not observed in a 3-repeat G55R tau versus 3-repeat wild-type tau comparison. In contrast, the G55R mutation has no effect upon the abilities of tau to regulate MT growing and shortening dynamics or to aggregate. Additionally, the mutation has no effect upon kinesin translocation in a microtubule gliding assay. Together, (i) we have identified a novel tau mutation mapping to a mutation deficient region of the protein in a bvFTD patient, and (ii) the G55R mutation affects the ability of tau to nucleate microtubule assembly in vitro in a 4-repeat tau isoform specific manner. This altered capability could markedly affect in vivo microtubule function and neuronal cell biology. We consider G55R to be a candidate mutation for bvFTD since additional criteria required to establish causality are not yet available for assessment.Abhinaya IyerNichole E LapointeKrzysztof ZielkeMariusz BerdynskiElmer GuzmanAnna BarczakMałgorzata Chodakowska-ŻebrowskaMaria BarcikowskaStuart FeinsteinCezary ZekanowskiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 9, p e76409 (2013) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Abhinaya Iyer Nichole E Lapointe Krzysztof Zielke Mariusz Berdynski Elmer Guzman Anna Barczak Małgorzata Chodakowska-Żebrowska Maria Barcikowska Stuart Feinstein Cezary Zekanowski A novel MAPT mutation, G55R, in a frontotemporal dementia patient leads to altered Tau function. |
| description |
Over two dozen mutations in the gene encoding the microtubule associated protein tau cause a variety of neurodegenerative dementias known as tauopathies, including frontotemporal dementia (FTD), PSP, CBD and Pick's disease. The vast majority of these mutations map to the C-terminal region of tau possessing microtubule assembly and microtubule dynamics regulatory activities as well as the ability to promote pathological tau aggregation. Here, we describe a novel and non-conservative tau mutation (G55R) mapping to an alternatively spliced exon encoding part of the N-terminal region of the protein in a patient with the behavioral variant of FTD. Although less well understood than the C-terminal region of tau, the N-terminal region can influence both MT mediated effects as well as tau aggregation. The mutation changes an uncharged glycine to a basic arginine in the midst of a highly conserved and very acidic region. In vitro, 4-repeat G55R tau nucleates microtubule assembly more effectively than wild-type 4-repeat tau; surprisingly, this effect is tau isoform specific and is not observed in a 3-repeat G55R tau versus 3-repeat wild-type tau comparison. In contrast, the G55R mutation has no effect upon the abilities of tau to regulate MT growing and shortening dynamics or to aggregate. Additionally, the mutation has no effect upon kinesin translocation in a microtubule gliding assay. Together, (i) we have identified a novel tau mutation mapping to a mutation deficient region of the protein in a bvFTD patient, and (ii) the G55R mutation affects the ability of tau to nucleate microtubule assembly in vitro in a 4-repeat tau isoform specific manner. This altered capability could markedly affect in vivo microtubule function and neuronal cell biology. We consider G55R to be a candidate mutation for bvFTD since additional criteria required to establish causality are not yet available for assessment. |
| format |
article |
| author |
Abhinaya Iyer Nichole E Lapointe Krzysztof Zielke Mariusz Berdynski Elmer Guzman Anna Barczak Małgorzata Chodakowska-Żebrowska Maria Barcikowska Stuart Feinstein Cezary Zekanowski |
| author_facet |
Abhinaya Iyer Nichole E Lapointe Krzysztof Zielke Mariusz Berdynski Elmer Guzman Anna Barczak Małgorzata Chodakowska-Żebrowska Maria Barcikowska Stuart Feinstein Cezary Zekanowski |
| author_sort |
Abhinaya Iyer |
| title |
A novel MAPT mutation, G55R, in a frontotemporal dementia patient leads to altered Tau function. |
| title_short |
A novel MAPT mutation, G55R, in a frontotemporal dementia patient leads to altered Tau function. |
| title_full |
A novel MAPT mutation, G55R, in a frontotemporal dementia patient leads to altered Tau function. |
| title_fullStr |
A novel MAPT mutation, G55R, in a frontotemporal dementia patient leads to altered Tau function. |
| title_full_unstemmed |
A novel MAPT mutation, G55R, in a frontotemporal dementia patient leads to altered Tau function. |
| title_sort |
novel mapt mutation, g55r, in a frontotemporal dementia patient leads to altered tau function. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/f20d01dc6d6a4752b89ec843954ba1dc |
| work_keys_str_mv |
AT abhinayaiyer anovelmaptmutationg55rinafrontotemporaldementiapatientleadstoalteredtaufunction AT nicholeelapointe anovelmaptmutationg55rinafrontotemporaldementiapatientleadstoalteredtaufunction AT krzysztofzielke anovelmaptmutationg55rinafrontotemporaldementiapatientleadstoalteredtaufunction AT mariuszberdynski anovelmaptmutationg55rinafrontotemporaldementiapatientleadstoalteredtaufunction AT elmerguzman anovelmaptmutationg55rinafrontotemporaldementiapatientleadstoalteredtaufunction AT annabarczak anovelmaptmutationg55rinafrontotemporaldementiapatientleadstoalteredtaufunction AT małgorzatachodakowskazebrowska anovelmaptmutationg55rinafrontotemporaldementiapatientleadstoalteredtaufunction AT mariabarcikowska anovelmaptmutationg55rinafrontotemporaldementiapatientleadstoalteredtaufunction AT stuartfeinstein anovelmaptmutationg55rinafrontotemporaldementiapatientleadstoalteredtaufunction AT cezaryzekanowski anovelmaptmutationg55rinafrontotemporaldementiapatientleadstoalteredtaufunction AT abhinayaiyer novelmaptmutationg55rinafrontotemporaldementiapatientleadstoalteredtaufunction AT nicholeelapointe novelmaptmutationg55rinafrontotemporaldementiapatientleadstoalteredtaufunction AT krzysztofzielke novelmaptmutationg55rinafrontotemporaldementiapatientleadstoalteredtaufunction AT mariuszberdynski novelmaptmutationg55rinafrontotemporaldementiapatientleadstoalteredtaufunction AT elmerguzman novelmaptmutationg55rinafrontotemporaldementiapatientleadstoalteredtaufunction AT annabarczak novelmaptmutationg55rinafrontotemporaldementiapatientleadstoalteredtaufunction AT małgorzatachodakowskazebrowska novelmaptmutationg55rinafrontotemporaldementiapatientleadstoalteredtaufunction AT mariabarcikowska novelmaptmutationg55rinafrontotemporaldementiapatientleadstoalteredtaufunction AT stuartfeinstein novelmaptmutationg55rinafrontotemporaldementiapatientleadstoalteredtaufunction AT cezaryzekanowski novelmaptmutationg55rinafrontotemporaldementiapatientleadstoalteredtaufunction |
| _version_ |
1718421238279307264 |