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Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency A Randomized Clinical Trial KU Leuven
IMPORTANCE: Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations. OBJECTIVE: To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and ...
Peripheral progranulin levels do not reflect brain progranulin levels KU Leuven
© 2014 Future Medicine Ltd. EVALUATION OF: Nicholson AM, Finch NA, Thomas CS et al. Progranulin protein levels are differently regulated in plasma and CSF. Neurology 82(21), 1871-1878 (2014). Nicholson et al. report the first population-based comparative study of progranulin (GRN) levels in plasma and cerebrospinal fluid (CSF) in a large human cohort. Age, sex and rs5848 were found to be important modifiers of GRN levels in both plasma and CSF. ...
Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members University of Antwerp
Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD) with ubiquitin and TAR DNA-binding protein 43 (TDP43)-positive pathology. The clinical presentation associated with GRN mutations is heterogeneous and may include clinical probable Alzheimers disease. All GRN mutations identified thus far cause disease through a uniform disease mechanism, i.e. the loss of functional GRN or ...
Promoter DNA methylation regulates progranulin expression and is altered in FTLD Vrije Universiteit Brussel University of Antwerp
BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of neurodegenerative diseases associated with personality changes and progressive dementia. Loss-of-function mutations in the growth factor progranulin (GRN) cause autosomal dominant FTLD, but so far the pathomechanism of sporadic FTLD is unclear.
RESULTS: We analyzed whether DNA methylation in the GRN core promoter restricts GRN expression and, thus, might ...
Progranulin variability has no major role in Parkinson disease genetic etiology Vrije Universiteit Brussel
Progranullin locus deletion in frontotemporal dementia Vrije Universiteit Brussel University of Antwerp
Soluble sortilin is present in excess and positively correlates with progranulin in CSF of aging individuals University of Antwerp
Mutations in progranulin are a major cause of frontotemporal lobe degeneration (FTLD). Hence, plasma progranulin is an attractive biomarker in FTLD but poorly reflects levels in cerebrospinal fluid (CSF), suggesting tissue-specific regulation of progranulin levels. Sortilin was recently identified as a progranulin scavenger receptor that destines it for lysosomal degradation. Proteolysis or alternative splicing generates soluble sortilin ...
Progranulin is neurotrophic in vivo and protects against a mutant TDP-43 induced axonopathy KU Leuven
Mislocalization, aberrant processing and aggregation of TAR DNA-binding protein 43 (TDP-43) is found in the neurons affected by two related diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal lobe dementia (FTLD). These TDP-43 abnormalities are seen when TDP-43 is mutated, such as in familial ALS, but also in FTLD, caused by null mutations in the progranulin gene. They are also found in many patients with sporadic ALS and FTLD, ...
Human Genetics as a Tool to Identify Progranulin Regulators University of Antwerp
Frontotemporal lobar degeneration (FTLD) is a common neurodegenerative disorder that predominantly affects individuals under the age of 65. It is known that the most common pathological subtype is FTLD with TAR DNA-binding protein 43 inclusions (FTLD-TDP). FTLD has a strong genetic component with about 50% of cases having a positive family history. Mutations identified in the progranulin gene (GRN) have been shown to cause FTLD-TDP as a result ...