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Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice.

Yin F, Banerjee R, Thomas B, Zhou P, Qian L, Jia T, Ma X, Ma Y, Iadecola C, Beal MF, Nathan C, Ding A - J. Exp. Med. (2009)

Bottom Line: PGRN-deficient macrophages and microglia were cytotoxic to hippocampal cells in vitro, and PGRN-deficient hippocampal slices were hypersusceptible to deprivation of oxygen and glucose.Thus, PGRN is a key regulator of inflammation and plays critical roles in both host defense and neuronal integrity.FTD associated with PGRN insufficiency may result from many years of reduced neutrotrophic support together with cumulative damage in association with dysregulated inflammation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA.

ABSTRACT
Progranulin (PGRN) is a widely expressed protein involved in diverse biological processes. Haploinsufficiency of PGRN in the human causes tau-negative, ubiquitin-positive frontotemporal dementia (FTD). However, the mechanisms are unknown. To explore the role of PGRN in vivo, we generated PGRN-deficient mice. Macrophages from these mice released less interleukin-10 and more inflammatory cytokines than wild type (WT) when exposed to bacterial lipopolysaccharide. PGRN-deficient mice failed to clear Listeria monocytogenes infection as quickly as WT and allowed bacteria to proliferate in the brain, with correspondingly greater inflammation than in WT. PGRN-deficient macrophages and microglia were cytotoxic to hippocampal cells in vitro, and PGRN-deficient hippocampal slices were hypersusceptible to deprivation of oxygen and glucose. With age, brains of PGRN-deficient mice displayed greater activation of microglia and astrocytes than WT, and their hippocampal and thalamic neurons accumulated cytosolic phosphorylated transactivation response element DNA binding protein-43. Thus, PGRN is a key regulator of inflammation and plays critical roles in both host defense and neuronal integrity. FTD associated with PGRN insufficiency may result from many years of reduced neutrotrophic support together with cumulative damage in association with dysregulated inflammation.

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Increased ubiquitination and phosphorylation of TDP-43 in the PGRN-deficient brain. (A) Enhanced ubiquitin immunostaining in the hippocampus of old PGRN-deficient mice. Sections from 18-mo-old WT and PGRN-deficient (KO) mice (n = 5) were stained using antibody against ubiquitin. Representative sections from two different mice in each group are shown. Bar, 80 µm. (B) Phosphorylation of TDP-43 and its cytosolic translocation in aged PGRN-deficient (KO) mice. Hippocampal and thalamic sections from 18-mo-old WT and PGRN-deficient mice (n = 5) were stained with antibodies against TDP-43 (top) or phosphorylated TDP-43 (bottom). Bars: (left and middle) 80 µm; (right) 12 µm.
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fig7: Increased ubiquitination and phosphorylation of TDP-43 in the PGRN-deficient brain. (A) Enhanced ubiquitin immunostaining in the hippocampus of old PGRN-deficient mice. Sections from 18-mo-old WT and PGRN-deficient (KO) mice (n = 5) were stained using antibody against ubiquitin. Representative sections from two different mice in each group are shown. Bar, 80 µm. (B) Phosphorylation of TDP-43 and its cytosolic translocation in aged PGRN-deficient (KO) mice. Hippocampal and thalamic sections from 18-mo-old WT and PGRN-deficient mice (n = 5) were stained with antibodies against TDP-43 (top) or phosphorylated TDP-43 (bottom). Bars: (left and middle) 80 µm; (right) 12 µm.

Mentions: A neuropathological feature associated with PGRN-haploinsufficient FTD is the appearance of ubiquitin-positive neuronal cytoplasmic and intranuclear inclusions (Mackenzie et al., 2006), whose major component is TDP-43 (Neumann et al., 2006). We found that staining for ubiquitin was elevated in the hippocampus and thalamus but not other regions of 18-mo-old WT and PGRN-deficient mice, but was much more pronounced in PGRN-deficient mice (Fig. 7 A and Fig. S5). In our study, nuclear TDP-43 was detected in the hippocampus and thalamus at a similar level in WT and PGRN-deficient mice using a polyclonal antibody against full-length TDP-43 (Fig. 7 B, top). Whether TDP-43 colocalized with ubiquitin was difficult to confirm, because ubiquitination of autofluorescent lipofuscin was increased in the absence of PGRN (Lewis et al., 2009). However, the most striking change was the appearance of phospho–TDP-43 in the cytosol of neurons in the dentate gyrus and thalamus of aged PGRN-deficient but not aged WT mice (Fig. 7 B) or young PGRN-deficient mice (not depicted).


Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice.

Yin F, Banerjee R, Thomas B, Zhou P, Qian L, Jia T, Ma X, Ma Y, Iadecola C, Beal MF, Nathan C, Ding A - J. Exp. Med. (2009)

Increased ubiquitination and phosphorylation of TDP-43 in the PGRN-deficient brain. (A) Enhanced ubiquitin immunostaining in the hippocampus of old PGRN-deficient mice. Sections from 18-mo-old WT and PGRN-deficient (KO) mice (n = 5) were stained using antibody against ubiquitin. Representative sections from two different mice in each group are shown. Bar, 80 µm. (B) Phosphorylation of TDP-43 and its cytosolic translocation in aged PGRN-deficient (KO) mice. Hippocampal and thalamic sections from 18-mo-old WT and PGRN-deficient mice (n = 5) were stained with antibodies against TDP-43 (top) or phosphorylated TDP-43 (bottom). Bars: (left and middle) 80 µm; (right) 12 µm.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2812536&req=5

fig7: Increased ubiquitination and phosphorylation of TDP-43 in the PGRN-deficient brain. (A) Enhanced ubiquitin immunostaining in the hippocampus of old PGRN-deficient mice. Sections from 18-mo-old WT and PGRN-deficient (KO) mice (n = 5) were stained using antibody against ubiquitin. Representative sections from two different mice in each group are shown. Bar, 80 µm. (B) Phosphorylation of TDP-43 and its cytosolic translocation in aged PGRN-deficient (KO) mice. Hippocampal and thalamic sections from 18-mo-old WT and PGRN-deficient mice (n = 5) were stained with antibodies against TDP-43 (top) or phosphorylated TDP-43 (bottom). Bars: (left and middle) 80 µm; (right) 12 µm.
Mentions: A neuropathological feature associated with PGRN-haploinsufficient FTD is the appearance of ubiquitin-positive neuronal cytoplasmic and intranuclear inclusions (Mackenzie et al., 2006), whose major component is TDP-43 (Neumann et al., 2006). We found that staining for ubiquitin was elevated in the hippocampus and thalamus but not other regions of 18-mo-old WT and PGRN-deficient mice, but was much more pronounced in PGRN-deficient mice (Fig. 7 A and Fig. S5). In our study, nuclear TDP-43 was detected in the hippocampus and thalamus at a similar level in WT and PGRN-deficient mice using a polyclonal antibody against full-length TDP-43 (Fig. 7 B, top). Whether TDP-43 colocalized with ubiquitin was difficult to confirm, because ubiquitination of autofluorescent lipofuscin was increased in the absence of PGRN (Lewis et al., 2009). However, the most striking change was the appearance of phospho–TDP-43 in the cytosol of neurons in the dentate gyrus and thalamus of aged PGRN-deficient but not aged WT mice (Fig. 7 B) or young PGRN-deficient mice (not depicted).

Bottom Line: PGRN-deficient macrophages and microglia were cytotoxic to hippocampal cells in vitro, and PGRN-deficient hippocampal slices were hypersusceptible to deprivation of oxygen and glucose.Thus, PGRN is a key regulator of inflammation and plays critical roles in both host defense and neuronal integrity.FTD associated with PGRN insufficiency may result from many years of reduced neutrotrophic support together with cumulative damage in association with dysregulated inflammation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA.

ABSTRACT
Progranulin (PGRN) is a widely expressed protein involved in diverse biological processes. Haploinsufficiency of PGRN in the human causes tau-negative, ubiquitin-positive frontotemporal dementia (FTD). However, the mechanisms are unknown. To explore the role of PGRN in vivo, we generated PGRN-deficient mice. Macrophages from these mice released less interleukin-10 and more inflammatory cytokines than wild type (WT) when exposed to bacterial lipopolysaccharide. PGRN-deficient mice failed to clear Listeria monocytogenes infection as quickly as WT and allowed bacteria to proliferate in the brain, with correspondingly greater inflammation than in WT. PGRN-deficient macrophages and microglia were cytotoxic to hippocampal cells in vitro, and PGRN-deficient hippocampal slices were hypersusceptible to deprivation of oxygen and glucose. With age, brains of PGRN-deficient mice displayed greater activation of microglia and astrocytes than WT, and their hippocampal and thalamic neurons accumulated cytosolic phosphorylated transactivation response element DNA binding protein-43. Thus, PGRN is a key regulator of inflammation and plays critical roles in both host defense and neuronal integrity. FTD associated with PGRN insufficiency may result from many years of reduced neutrotrophic support together with cumulative damage in association with dysregulated inflammation.

Show MeSH
Related in: MedlinePlus