Loss of nuclear activity of the FBXO7 protein in patients with parkinsonian-pyramidal syndrome (PARK15).

Mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, an autosomal recessive neurodegenerative disease presenting with severe levodopa-responsive parkinsonism and pyramidal disturbances. Understanding the PARK15 pathogenesis might thus provide clues on the mechanisms of maintenance of bra...

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Autores principales:	Tianna Zhao, Esther De Graaff, Guido J Breedveld, Agnese Loda, Lies-Anne Severijnen, Cokkie H Wouters, Frans W Verheijen, Marieke C J Dekker, Pasquale Montagna, Rob Willemsen, Ben A Oostra, Vincenzo Bonifati
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/79ff1dcbf60b48248d53e36d35d1a7d6
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spelling	oai:doaj.org-article:79ff1dcbf60b48248d53e36d35d1a7d62021-11-18T06:58:54ZLoss of nuclear activity of the FBXO7 protein in patients with parkinsonian-pyramidal syndrome (PARK15).1932-620310.1371/journal.pone.0016983https://doaj.org/article/79ff1dcbf60b48248d53e36d35d1a7d62011-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21347293/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, an autosomal recessive neurodegenerative disease presenting with severe levodopa-responsive parkinsonism and pyramidal disturbances. Understanding the PARK15 pathogenesis might thus provide clues on the mechanisms of maintenance of brain dopaminergic neurons, the same which are lost in Parkinson's disease. The protein(s) encoded by FBXO7 remain very poorly characterized. Here, we show that two protein isoforms are expressed from the FBXO7 gene in normal human cells. The isoform 1 is more abundant, particularly in primary skin fibroblasts. Both isoforms are undetectable in cell lines from the PARK15 patient of an Italian family; the isoform 1 is undetectable and the isoform 2 is severely decreased in the patients from a Dutch PARK15 family. In human cell lines and mouse primary neurons, the endogenous or over-expressed, wild type FBXO7 isoform 1 displays mostly a diffuse nuclear localization. An intact N-terminus is needed for the nuclear FBXO7 localization, as N-terminal modification by PARK15-linked missense mutation, or N-terminus tag leads to cytoplasmic mislocalization. Furthermore, the N-terminus of wild type FBXO7 (but not of mutant FBXO7) is able to confer nuclear localization to profilin (a cytoplasmic protein). Our data also suggest that overexpressed mutant FBXO7 proteins (T22M, R378G and R498X) have decreased stability compared to their wild type counterpart. In human brain, FBXO7 immunoreactivity was highest in the nuclei of neurons throughout the cerebral cortex, intermediate in the globus pallidum and the substantia nigra, and lowest in the hippocampus and cerebellum. In conclusion, the common cellular abnormality found in the PARK15 patients from the Dutch and Italian families is the depletion of the FBXO7 isoform 1, which normally localizes in the cell nucleus. The activity of FBXO7 in the nucleus appears therefore crucial for the maintenance of brain neurons and the pathogenesis of PARK15.Tianna ZhaoEsther De GraaffGuido J BreedveldAgnese LodaLies-Anne SeverijnenCokkie H WoutersFrans W VerheijenMarieke C J DekkerPasquale MontagnaRob WillemsenBen A OostraVincenzo BonifatiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 2, p e16983 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tianna Zhao Esther De Graaff Guido J Breedveld Agnese Loda Lies-Anne Severijnen Cokkie H Wouters Frans W Verheijen Marieke C J Dekker Pasquale Montagna Rob Willemsen Ben A Oostra Vincenzo Bonifati Loss of nuclear activity of the FBXO7 protein in patients with parkinsonian-pyramidal syndrome (PARK15).
description	Mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, an autosomal recessive neurodegenerative disease presenting with severe levodopa-responsive parkinsonism and pyramidal disturbances. Understanding the PARK15 pathogenesis might thus provide clues on the mechanisms of maintenance of brain dopaminergic neurons, the same which are lost in Parkinson's disease. The protein(s) encoded by FBXO7 remain very poorly characterized. Here, we show that two protein isoforms are expressed from the FBXO7 gene in normal human cells. The isoform 1 is more abundant, particularly in primary skin fibroblasts. Both isoforms are undetectable in cell lines from the PARK15 patient of an Italian family; the isoform 1 is undetectable and the isoform 2 is severely decreased in the patients from a Dutch PARK15 family. In human cell lines and mouse primary neurons, the endogenous or over-expressed, wild type FBXO7 isoform 1 displays mostly a diffuse nuclear localization. An intact N-terminus is needed for the nuclear FBXO7 localization, as N-terminal modification by PARK15-linked missense mutation, or N-terminus tag leads to cytoplasmic mislocalization. Furthermore, the N-terminus of wild type FBXO7 (but not of mutant FBXO7) is able to confer nuclear localization to profilin (a cytoplasmic protein). Our data also suggest that overexpressed mutant FBXO7 proteins (T22M, R378G and R498X) have decreased stability compared to their wild type counterpart. In human brain, FBXO7 immunoreactivity was highest in the nuclei of neurons throughout the cerebral cortex, intermediate in the globus pallidum and the substantia nigra, and lowest in the hippocampus and cerebellum. In conclusion, the common cellular abnormality found in the PARK15 patients from the Dutch and Italian families is the depletion of the FBXO7 isoform 1, which normally localizes in the cell nucleus. The activity of FBXO7 in the nucleus appears therefore crucial for the maintenance of brain neurons and the pathogenesis of PARK15.
format	article
author	Tianna Zhao Esther De Graaff Guido J Breedveld Agnese Loda Lies-Anne Severijnen Cokkie H Wouters Frans W Verheijen Marieke C J Dekker Pasquale Montagna Rob Willemsen Ben A Oostra Vincenzo Bonifati
author_facet	Tianna Zhao Esther De Graaff Guido J Breedveld Agnese Loda Lies-Anne Severijnen Cokkie H Wouters Frans W Verheijen Marieke C J Dekker Pasquale Montagna Rob Willemsen Ben A Oostra Vincenzo Bonifati
author_sort	Tianna Zhao
title	Loss of nuclear activity of the FBXO7 protein in patients with parkinsonian-pyramidal syndrome (PARK15).
title_short	Loss of nuclear activity of the FBXO7 protein in patients with parkinsonian-pyramidal syndrome (PARK15).
title_full	Loss of nuclear activity of the FBXO7 protein in patients with parkinsonian-pyramidal syndrome (PARK15).
title_fullStr	Loss of nuclear activity of the FBXO7 protein in patients with parkinsonian-pyramidal syndrome (PARK15).
title_full_unstemmed	Loss of nuclear activity of the FBXO7 protein in patients with parkinsonian-pyramidal syndrome (PARK15).
title_sort	loss of nuclear activity of the fbxo7 protein in patients with parkinsonian-pyramidal syndrome (park15).
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/79ff1dcbf60b48248d53e36d35d1a7d6
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Loss of nuclear activity of the FBXO7 protein in patients with parkinsonian-pyramidal syndrome (PARK15).

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