The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene.
ABSTRACT The most common pathology in frontotemporal dementia (FTD) is tau-negative, ubiquitin-immunoreactive (ub-ir) neuronal inclusions (FTLD-U). Recently, we identified mutations in the progranulin (PGRN) gene as the cause of autosomal dominant FTLD-U linked to chromosome 17. Here, we describe the neuropathology in 13 patients from 6 different families, each with FTD caused by a different PGRN mutation. The most consistent feature was the presence of ub-ir lentiform neuronal intranuclear inclusions (NII) in the neocortex and striatum. In addition, the neocortex showed moderate-to-severe superficial laminar spongiosis, chronic degenerative changes, ub-ir neurites and well-defined ub-ir neuronal cytoplasmic inclusions (NCI). In the striatum, there were numerous ub-ir neurites. NCI in the hippocampus usually had a granular appearance. In contrast, familial FTLD-U cases without PGRN mutations had no NII, less severe neocortical and striatal pathology and hippocampal NCI that were more often solid. Eight cases in which genetic analysis was not available also had NII and an overall pathology similar to those with proven mutations. None of our cases of FTLD-U without NII showed the same pattern of pathology as those with mutations. These findings suggest that FTD caused by PGRN mutations has a recognizable pathology with the most characteristic feature being ub-ir NII.
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ABSTRACT: Loss of function mutations in granulin (GRN) are linked to two distinct neurological disorders, frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL). It is so far unknown how a complete loss of GRN in NCL and partial loss of GRN in FTLD can result in such distinct diseases. In zebrafish, there are two GRN homologues, Granulin A (Grna) and Granulin B (Grnb). We have generated stable Grna and Grnb loss of function zebrafish mutants by zinc finger nuclease mediated genome editing. Surprisingly, the grna and grnb single and double mutants display neither spinal motor neuron axonopathies nor a reduced number of myogenic progenitor cells as previously reported for Grna and Grnb knock down embryos. Additionally, grna-/-;grnb-/- double mutants have no obvious FTLD- and NCL-related biochemical and neuropathological phenotypes. Taken together, the Grna and Grnb single and double knock out zebrafish lack any obvious morphological, pathological and biochemical phenotypes. Loss of zebrafish Grna and Grnb might therefore either be fully compensated or only become symptomatic upon additional challenge.PLoS ONE 01/2015; 10(3):e0118956. DOI:10.1371/journal.pone.0118956 · 3.53 Impact Factor
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ABSTRACT: The concept that frontotemporal dementia (FTD) is a purely cortical dementia has largely been refuted by the recognition of its close association with motor neuron disease, and the identification of transactive response DNA-binding protein 43 (TDP-43) as a major pathological substrate underlying both diseases. Genetic findings have transformed this field and revealed connections between disorders that were previous thought clinically unrelated. The discovery that the C9ORF72 locus is responsible for the majority of hereditary FTD, amyotrophic lateral sclerosis (ALS), and FTD–ALS cases and the understanding that repeat-containing RNA plays a crucial role in pathogenesis of both disorders has paved the way for the development of potential biomarkers and therapeutic targets for these devastating diseases. In this review, we summarize the historical aspects leading up to our current understanding of the genetic, clinical, and neuropathological overlap between FTD and ALS, and include brief discussions on chronic traumatic encephalopathy (CTE), given its association with TDP-43 pathology, its associated increased dementia risk, and reports of ALS in CTE patients. In addition, we describe other genetic associations between dementia and neuromuscular disease, such as inclusion body myositis with Paget's disease and FTD.Annals of the New York Academy of Sciences 12/2014; 1338(1). DOI:10.1111/nyas.12638 · 4.31 Impact Factor
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ABSTRACT: Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by degeneration of the fronto temporal lobes and abnormal protein inclusions. It exhibits a broad clinicopathological spectrum and has been linked to mutations in seven different genes. We will provide a picture, which connects the products of these genes, albeit diverse in nature and function, in a network. Despite the paucity of information available for some of these genes, we believe that RNA processing and post-transcriptional regulation of gene expression might constitute a common theme in the network. Recent studies have unraveled the role of mutations affecting the functions of RNA binding proteins and regulation of microRNAs. This review will combine all the recent findings on genes involved in the pathogenesis of FTD, highlighting the importance of a common network of interactions in order to study and decipher the heterogeneous clinical manifestations associated with FTD. This approach could be helpful for the research of potential therapeutic strategies.Frontiers in Molecular Neuroscience 03/2015; 8:9. DOI:10.3389/fnmol.2015.00009