Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementia

Yin, Fang‐Fang; Dumont, Magali; Banerjee, Rebecca; Ma, Yao; Li, Huihong; Lin, Michael; Beal, M. Flint; Nathan, Carl; Thomas, Bobby; Ding, Aihao

doi:10.1096/fj.10-161471

Cited by 150 publications

(157 citation statements)

References 28 publications

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“…This is consistent with the large number of activated CD68 positive microglia in GRN mouse models (Lui et al, 2016; Martens et al, 2012; Yin et al, 2009, 2010) and patients with GRN mutations, especially in frontal white matter (Lant et al, 2014; Taipa et al, 2017), which could cause white matter damage through excessive phagocytosis. We also identified many amoeboid CR3/43 positive microglia in areas of severe WMH, suggesting that microglia with antigen-presenting cell function were particularly active in these regions, which has not been described previously in FTD.…”

Section: Discussionsupporting

confidence: 78%

Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

et al. 2018

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White matter hyperintensities (WMH) are often seen on MRI brain scans in frontotemporal dementia (FTD) due to progranulin (GRN) mutations, but their pathological correlates are unknown. We examined the histological changes underlying WMH in a patient with GRN mutation associated behavioral variant FTD. In vivo and cadaveric MRI showed progressive, asymmetric frontotemporal and parietal atrophy, and asymmetrical WMH predominantly affecting frontal mid-zones. We first performed segmentation and localization analyses of WMH present on cadaveric MRI FLAIR images, then selected five different brain regions directly matched to differing severities of WMH for histological analysis. We used immunohistochemistry to assess vascular pathology, degree of spongiosis, neuronal and axonal loss, TDP-43, demyelination and astrogliosis, and microglial burden and morphology. Brain regions with significant WMH displayed severe cortical and white matter pathology, and prominent white matter microglial activation and microglial dystrophy, but only mild axonal loss and minimal vascular pathology. Our study suggests that WMH in GRN mutation carriers are not secondary to vascular pathology. Whilst cortical pathology induced axonal degeneration could contribute to white matter damage, individuals with GRN mutations could develop selective white matter vulnerability and myelin loss due to chronic, regional microglial dysfunction arising from GRN haploinsufficiency.

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Section: Discussionsupporting

confidence: 78%

Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

et al. 2018

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“…in the brain (Ahmed et al, 2010;Yin et al, 2010), we observed progressive, substantial thinning of the RNFL and a loss of ganglion cell layer (GCL) cells in 18-mo-old Grn-KO mice (Fig. 1, H-J).…”

Section: Results and Discussion Early Retinal Abnormalities In Humansmentioning

confidence: 87%

“…Mutations in the GRN gene that cause progranulin haploinsufficiency are a common cause of familial FTLD-TDP (Baker et al, 2006). Aged Grn-KO mice exhibit FTD-like behavioral abnormalities but lack TDP-43 mislocalization or neurodegeneration in cortical regions (Ahmed et al, 2010;Yin et al, 2010;Martens et al, 2012).…”

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confidence: 99%

Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD

Ward¹,

Taubes²,

Chen³

et al. 2014

J Cell Biol

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“…Disruption of both the ubiquitin-proteasome system and the autophagy-lysosomal system is one of the characteristic features of FTLD with TDP-43 inclusions in the cytoplasm of neurons [27], and impaired production of PGRN is involved in this pathology [5][6][7]. Previous studies reported increased TDP-43 phosphorylation in PGRN-deficient mice [11,13,28]. In the present study, TDP-43 colocalized with p62 in the cytoplasm of neurons as well as the phosphorylated TDP-43 aggregate in the VPM/VPL were only observed in aged PGRN-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice

Tanaka

Chambers

Matsuwaki

et al. 2014

Acta Neuropathologica Communications

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Introduction: It has been shown that progranulin (PGRN) deficiency causes age-related neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Previous studies also suggested that PGRN is involved in modulating lysosomal function. To elucidate the pathophysiological role of PGRN in the aged brain, in the present study, lysosomal function and pathological changes of the brain were investigated using 10-and 90-week-old wild-type and PGRN-deficient mice. Results: We showed that PGRN deficiency caused enhanced CD68 expression in activated microglia and astrogliosis in the cortex and thalamus, especially in the ventral posteromedial nucleus/ventral posterolateral nucleus (VPM/VPL), in the aged brain. Immunoreactivity for Lamp1 (lysosome marker) in the VPM/VPL and expression of lysosome-related genes, i.e. cathepsin D, V-type proton ATPase subunit d2, and transcription factor EB genes, were also increased by PGRN deficiency. Aggregates of p62, which is selectively degraded by the autophagy-lysosomal system, were observed in neuronal and glial cells in the VPM/VPL of aged PGRN-deficient mice. TAR DNA binding protein 43 (TDP-43) aggregates in the cytoplasm of neurons were also observed in aged PGRN-deficient mice. PGRN deficiency caused enhanced expression of glial cell-derived cytotoxic factors such as macrophage expressed gene 1, cytochrome b-245 light chain, cytochrome b-245 heavy chain, complement C4, tumor necrosis factor-α and lipocalin 2. In addition, neuronal loss and lipofuscinosis in the VPM/VPL and disrupted myelination in the cerebral cortex were observed in aged PGRN-deficient mice.

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Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementia

Cited by 150 publications

References 28 publications

Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD

Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice

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