Mackenzie, I. R. et al. The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain 129, 3081-3090

Department of Pathology and Laboratory Medicine, University of British Columbia and Vancouver Coastal Health Vancouver, BC, Canada.
Brain (Impact Factor: 9.2). 12/2006; 129(Pt 11):3081-90. DOI: 10.1093/brain/awl271
Source: PubMed


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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    • "However, all are predicted to result in reduction of functional progranulin (Baker et al., 2006; Cruts et al., 2006; Rademakers and Rovelet-Lecrux, 2009). Loss of progranulin function in these familial cases causes type A TDP-43 pathology (Mackenzie et al., 2006). Common genetic variants in progranulin are also potential risk factors for TDP-43 proteinopathies including sporadic FTLD (Brouwers et al., 2008; Sleegers et al., 2008; Galimberti et al., 2010). "
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    ABSTRACT: In the search for therapeutic modifiers, frontotemporal dementia (FTD) has traditionally been overshadowed by other conditions such as Alzheimer's disease (AD). A clinically and pathologically diverse condition, FTD has been galvanized by a number of recent discoveries such as novel genetic variants in familial and sporadic forms of disease and the identification of TAR DNA binding protein of 43 kDa (TDP-43) as the defining constituent of inclusions in more than half of cases. In combination with an ever-expanding knowledge of the function and dysfunction of tau—a protein which is pathologically aggregated in the majority of the remaining cases—there exists a greater understanding of FTD than ever before. These advances may indicate potential approaches for the development of hypothetical therapeutics, but FTD remains highly complex and the roles of tau and TDP-43 in neurodegeneration are still wholly unclear. Here the challenges facing potential therapeutic strategies are discussed, which include sufficiently accurate disease diagnosis and sophisticated technology to deliver effective therapies.
    Full-text · Article · Aug 2014 · Frontiers in Aging Neuroscience
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    • "Progranulin is a multi-functional secreted protein with neuroprotective functions and its upregulation after nerve injury likely contributes to those adaptations, which combat the development of chronic pain (Lim et al., 2012). Loss-of-function mutations of progranulin in humans are associated with ubiquitin positive, Tau-negative frontotemporal dementia and some other neurodegenerative diseases (Baker et al., 2006; Cruts et al., 2006; Mackenzie et al., 2006). It has not been studied if these patients experience stronger or longer lasting pain. "
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    ABSTRACT: Persistent neuropathic pain is a frequent consequence of peripheral nerve injuries, particularly in the elderly. Using the IntelliCage we studied if sciatic nerve injury obstructed learning and memory in young and aged mice, each in wild type and progranulin deficient mice, which develop premature signs of brain aging. Both young and aged mice developed long-term nerve injury-evoked hyperalgesia and allodynia. In both genotypes, aged mice with neuropathic pain showed high error rates in place avoidance acquisition tasks. However, once learnt, these aged mice with neuropathic pain showed a significantly stronger maintenance of the aversive memory. Nerve injury did not affect place preference behavior in neither genotype, neither in young nor aged mice. However, nerve injury in progranulin deficient mice impaired the learning of spatial sequences of awarded places, particularly in the aged mice. This task required a discrimination of clockwise and anti-clockwise sequences. The chaining failure occurred only in progranulin deficient mice after nerve injury, but not in sham operated or wildtype mice, suggesting that progranulin was particularly important for compensatory adaptations after nerve injury. In contrast, all aged mice with neuropathic pain, irrespective of the genotype, had a long maintenance of aversive memory suggesting a negative alliance and possibly mutual aggravation of chronic neuropathic pain and aversive memory at old age.
    Full-text · Article · Nov 2013 · Frontiers in Behavioral Neuroscience
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    • "There are several sources of pathological heterogeneity within FTLD-TDP. First, a number of genetic defects have been identified in these cases; many being caused by mutations of the progranulin (GRN) gene (Baker et al. 2006; Cruts et al. 2006; Mukherjee et al. 2006; Mackenzie et al. 2006a; Behrens et al. 2007; Rademakers and Hutton 2007). A less prevalent disorder, FTLD with valosin-containing protein (VCP) gene mutation (Forman et al. 2006), also has TDP-43 immunoreactive inclusions and recently, variants in the ubiquitin associated binding protein 1 (UBAP1) gene (Luty et al. 2008; Rollinson et al. 2009) were shown to have TDP-43 inclusions. "
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    ABSTRACT: Aims: Previous data suggest heterogeneity in laminar distribution of the pathology in the molecular disorder frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). To study this heterogeneity, we quantified the changes in density across the cortical laminae of neuronal cytoplasmic inclusions, glial inclusions, neuronal intranuclear inclusions, dystrophic neurites, surviving neurones, abnormally enlarged neurones, and vacuoles in regions of the frontal and temporal lobe. Methods: Changes in density of histological features across cortical gyri were studied in 10 sporadic cases of FTLD-TDP using quantitative methods and polynomial curve fitting. Results: Our data suggest that laminar neuropathology in sporadic FTLD-TDP is highly variable. Most commonly, neuronal cytoplasmic inclusions, dystrophic neurites and vacuolation were abundant in the upper laminae and glial inclusions, neuronal intranuclear inclusions, abnormally enlarged neurones, and glial cell nuclei in the lower laminae. TDP-43-immunoreactive inclusions affected more of the cortical profile in longer duration cases; their distribution varied with disease subtype, but was unrelated to Braak tangle score. Different TDP-43-immunoreactive inclusions were not spatially correlated. Conclusions: Laminar distribution of pathological features in 10 sporadic cases of FTLD-TDP is heterogeneous and may be accounted for, in part, by disease subtype and disease duration. In addition, the feedforward and feedback cortico-cortical connections may be compromised in FTLD-TDP.
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