The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene

Mackenzie, Ian R.; Baker, Matt; Pickering‐Brown, Stuart; Hsiung, Ging-Yuek Robin; Lindholm, Caroline; Dwosh, Emily; Gass, Jennifer; Cannon, Ashley; Rademakers, Rosa; Hutton, Mike; Feldman, Howard

doi:10.1093/brain/awl271

Cited by 277 publications

(209 citation statements)

References 60 publications

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“…The relationship between this family's ALS and the PGRN mutation is not entirely clear. These data suggest that in contrast to MAPT, MND associated with mutations in PGRN may be quite rare (Mackenzie et al 2006a;Josephs et al 2007). …”

Section: Clinical Considerationsmentioning

confidence: 88%

Prominent phenotypic variability associated with mutations in Progranulin

Kelley

Haidar

Boeve

et al. 2009

Neurobiology of Aging

162

141

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Mutations in progranulin (PGRN) are associated with frontotemporal dementia with or without parkinsonism. We describe the prominent phenotypic variability within and among eight kindreds evaluated at Mayo Clinic Rochester and/or Mayo Clinic Jacksonville in whom mutations in PGRN were found. All available clinical, genetic, neuroimaging and neuropathologic data was reviewed. Age of onset ranged from 49 to 88 years and disease duration ranged from 1 to 14 years. Clinical diagnoses included frontotemporal dementia (FTD), primary progressive aphasia, FTD with parkinsonism, parkinsonism, corticobasal syndrome, Alzheimer's disease, amnestic mild cognitive impairment, and others. One kindred exhibited maximal right cerebral hemispheric atrophy in all four affected individuals, while another had maximal left hemisphere involvement in all three of the affected. Neuropathologic examination of 13 subjects revealed frontotemporal lobar degeneration with ubiquitin-positive inclusions plus neuronal intranuclear inclusions in all cases. Age of onset, clinical phenotypes and MRI findings associated with most PGRN mutations varied

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Section: Clinical Considerationsmentioning

confidence: 88%

Prominent phenotypic variability associated with mutations in Progranulin

Kelley

Haidar

Boeve

et al. 2009

Neurobiology of Aging

162

141

View full text Add to dashboard Cite

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“…One exception is frontotemporal dementia, a neurologic disease involving behavioral and language problems, leading to memory deficits. Some familial cases reflect progranulin haploinsufficiency [165]. A recent study showed that the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) increased progranulin mRNA and protein expression in haploinsufficiency progranulin human cells [166], suggesting that increasing acetylation should be beneficial.…”

Section: Ad and Related Diseasesmentioning

confidence: 99%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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“…This may explain the parkinsonism that is frequently associated with the disease even in its early stages. There are some case reports describing the loss of pigmented neurons from the substantia nigra [9,15,19]. Here we describe a case of a patient with a rare splicing mutation in the GRN gene and unilateral caudate nucleus atrophy.…”

Section: Introductionmentioning

confidence: 87%