DNA Mutation of the progranulin (GRN) gene in familial frontotemporal lobar degeneration (FTLD): a study of the pathology of nine cases

Richard Armstrong

Research output: Chapter in Book/Report/Conference proceedingChapter (peer-reviewed)

Abstract

Frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP) is a neurodegenerative disease characterized by variable neocortical and allocortical atrophy principally affecting the frontal and temporal lobes. Histologically, there is neuronal loss, microvacuolation in the superficial cortical laminae, and a reactive astrocytosis. A variety of TDP-43 immunoreactive changes are present in FTLD-TDP including neuronal cytoplasmic inclusions (NCI), neuronal intranuclear inclusions (NII), dystrophic neurites (DN) and, oligodendroglial inclusions (GI). Many cases of familial FTLD-TDP are caused by DNA mutations of the progranulin (GRN) gene. Hence, the density, spatial patterns, and laminar distribution of the pathological changes were studied in nine cases of FLTD-TDP with GRN mutation. The densities of NCI and DN were greater in cases caused by GRN mutation compared with sporadic cases. In cortical regions, the commonest spatial pattern exhibited by the TDP-43 immunoreactive lesions was the presence of clusters of inclusions regularly distributed parallel to the pia mater. In approximately 50% of cortical gyri, the NCI exhibited a peak of density in the upper cortical laminae while the GI were commonly distributed across all laminae. The distribution of the NII and DN was variable, the most common pattern being a peak of NII density in the lower cortical laminae and DN in the upper cortical laminae. These results suggest in FTLD-TDP caused by GRN mutation: 1) there are greater densities of NCI and DN than in sporadic cases of the disease, 2) there is degeneration of the cortico-cortical and cortico-hippocampal pathways, and 3) cortical degeneration occurs across the cortical laminae, the various TDP-43 immunoreactive inclusions often being distributed in different cortical laminae.
LanguageEnglish
Title of host publicationDNA replication and mutation
EditorsRaymond P. Leitner
Place of PublicationNew York (US)
PublisherNova science
Pages45-66
Number of pages22
ISBN (Electronic)978-1-61942-455-5
ISBN (Print)978-1-61324-490-6, 1-61324-490-8
Publication statusPublished - Apr 2011

Publication series

NameDNA and Rna: Properties and Modifications, Functions and Interactions, Recombination and Applications
PublisherNova Science Publishers

Fingerprint

Frontotemporal Lobar Degeneration
Neurites
Inclusion Bodies
DNA-Binding Proteins
Intranuclear Inclusion Bodies
Pathology
Mutation
DNA
Genes
Pia Mater
Gliosis
Frontal Lobe
Temporal Lobe
Neurodegenerative Diseases
Atrophy

Keywords

  • frontotemporal lobar degeneration with TDP-43 proteinopathy
  • spatial topography
  • progranulin (GRN) mutation
  • TAR DNA-binding protein

Cite this

Armstrong, R. (2011). DNA Mutation of the progranulin (GRN) gene in familial frontotemporal lobar degeneration (FTLD): a study of the pathology of nine cases. In R. P. Leitner (Ed.), DNA replication and mutation (pp. 45-66). (DNA and Rna: Properties and Modifications, Functions and Interactions, Recombination and Applications). New York (US): Nova science.
Armstrong, Richard. / DNA Mutation of the progranulin (GRN) gene in familial frontotemporal lobar degeneration (FTLD) : a study of the pathology of nine cases. DNA replication and mutation. editor / Raymond P. Leitner. New York (US) : Nova science, 2011. pp. 45-66 (DNA and Rna: Properties and Modifications, Functions and Interactions, Recombination and Applications).
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Armstrong, R 2011, DNA Mutation of the progranulin (GRN) gene in familial frontotemporal lobar degeneration (FTLD): a study of the pathology of nine cases. in RP Leitner (ed.), DNA replication and mutation. DNA and Rna: Properties and Modifications, Functions and Interactions, Recombination and Applications, Nova science, New York (US), pp. 45-66.

DNA Mutation of the progranulin (GRN) gene in familial frontotemporal lobar degeneration (FTLD) : a study of the pathology of nine cases. / Armstrong, Richard.

DNA replication and mutation. ed. / Raymond P. Leitner. New York (US) : Nova science, 2011. p. 45-66 (DNA and Rna: Properties and Modifications, Functions and Interactions, Recombination and Applications).

Research output: Chapter in Book/Report/Conference proceedingChapter (peer-reviewed)

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AB - Frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP) is a neurodegenerative disease characterized by variable neocortical and allocortical atrophy principally affecting the frontal and temporal lobes. Histologically, there is neuronal loss, microvacuolation in the superficial cortical laminae, and a reactive astrocytosis. A variety of TDP-43 immunoreactive changes are present in FTLD-TDP including neuronal cytoplasmic inclusions (NCI), neuronal intranuclear inclusions (NII), dystrophic neurites (DN) and, oligodendroglial inclusions (GI). Many cases of familial FTLD-TDP are caused by DNA mutations of the progranulin (GRN) gene. Hence, the density, spatial patterns, and laminar distribution of the pathological changes were studied in nine cases of FLTD-TDP with GRN mutation. The densities of NCI and DN were greater in cases caused by GRN mutation compared with sporadic cases. In cortical regions, the commonest spatial pattern exhibited by the TDP-43 immunoreactive lesions was the presence of clusters of inclusions regularly distributed parallel to the pia mater. In approximately 50% of cortical gyri, the NCI exhibited a peak of density in the upper cortical laminae while the GI were commonly distributed across all laminae. The distribution of the NII and DN was variable, the most common pattern being a peak of NII density in the lower cortical laminae and DN in the upper cortical laminae. These results suggest in FTLD-TDP caused by GRN mutation: 1) there are greater densities of NCI and DN than in sporadic cases of the disease, 2) there is degeneration of the cortico-cortical and cortico-hippocampal pathways, and 3) cortical degeneration occurs across the cortical laminae, the various TDP-43 immunoreactive inclusions often being distributed in different cortical laminae.

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Armstrong R. DNA Mutation of the progranulin (GRN) gene in familial frontotemporal lobar degeneration (FTLD): a study of the pathology of nine cases. In Leitner RP, editor, DNA replication and mutation. New York (US): Nova science. 2011. p. 45-66. (DNA and Rna: Properties and Modifications, Functions and Interactions, Recombination and Applications).