Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice
© Tanaka et al.; licensee BioMed Central Ltd. 2014
Received: 16 May 2014
Accepted: 22 June 2014
Published: 15 July 2014
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.
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.
The present study shows that aged PGRN-deficient mice present with NCL-like pathology as well as TDP-43 aggregates in the VPM/VPL, where a particular vulnerability has been reported in NCL model mice. The present results also suggest that these pathological changes in the VPM/VPL are likely a result of lysosomal dysfunction. How PGRN prevents lysosomal dysfunction with aging remains to be elucidated.
KeywordsProgranulin Lysosome Aging TAR DNA binding protein 43 Neuronal ceroid lipofuscinosis
Progranulin (PGRN), which is a 68.5-kDa glycoprotein containing 7.5 tandem repeats of a cysteine-rich motif, is proteolytically processed into 6-kDa granulins (GRNs) []. PGRN is involved in multiple physiological functions and various disease processes, including autoimmune disorders, tumorigenesis, and insulin resistance [–]. In the human brain, haploinsufficiency of PGRN is one of the major factors causing frontotemporal lobar degeneration (FTLD) [,], which is characterized by ubiquitinated cytoplasmic inclusions containing TAR DNA binding protein 43 (TDP-43) []. However, the mechanism by which impaired production of PGRN causes the formation of TDP-43 inclusions in the cytoplasm is not yet fully understood.
We previously demonstrated that PGRN expression increases after traumatic brain injury (TBI) in mice, and the major source of PGRN is CD68-positive activated microglia []. PGRN deficiency induces exacerbated inflammatory responses that are associated with increased lysosomal biogenesis in activated microglia after TBI. Further, the expression of cytotoxic factors is increased in relation to increased lysosomal biogenesis, and neuronal damage is exacerbated in PGRN-deficient mice []. Because microglial activation characterized by morphologic and phenotypic changes also occurs with aging [], increased lysosomal biogenesis and cytotoxic factor production may occur with aging in activated microglia in PGRN-deficient mice. Wils et al. suggested that PGRN-deficient mice have a disrupted autophagy-lysosomal pathway with alterations in lysosomal homeostasis [].
Patients with a homozygous mutation in the GRN gene present with neuronal ceroid lipofuscinosis (NCL), a group of neurodegenerative lysosomal storage disorders []. Additionally, Götzl et al. (2014) recently revealed that FTLD patients due to PGRN deficiency have NCL-like pathology []. These reports suggest that disorders with aging from PGRN deficiency occur associated with lysosomal dysfunction. The NCLs display a relatively uniform phenotype in the central nervous system that is characterized by a dramatic loss of cortical neurons, pronounced gliosis, and accumulation of lysosomal autofluorescent lipopigments []. NCL model animals show a particular vulnerability early during disease progression in the sensory thalamocortical pathways, i.e., projections from the ventral posteromedial nucleus/ventral posterolateral nucleus (VPM/VPL) of the thalamus to the primary somatosensory barrelfield cortex (S1BF) []. Localized aggregation of activated microglia and astrocytes followed by neuronal cell loss occur in this area [–]. Impaired myelination also occurs as a feature of some NCL models such as mice deficient in palmitoyl-protein thioesterase 1 (Ppt1), ceroid-lipofuscinosis, neuronal 5 (Cln5), and ceroid-lipofuscinosis, neuronal 8 (Cln8) genes [,]. However, characterization of the brain pathology regarding NCL in the VPM/VPL has yet to be performed in PGRN-deficient mice.
In the present study, the effects of PGRN deficiency on age-associated lysosomal biogenesis and function, inflammatory responses, and TDP-43 aggregates in the cytoplasm were investigated. Further, the brain pathology regarding NCL was also characterized in aged PGRN-deficient mice.
Materials and methods
In this study, 10- and 90-week-old female wild-type (WT) and PGRN-deficient (KO) C57BL/6J mice were used. They were produced from breeding heterozygous pairs in our laboratory and were genotyped using previously described protocols []. Mice were maintained under controlled light (lights on, 07:00–19:00), temperature (23 ± 1°C), and humidity (55 ± 10%), and were given free access to food and water. All animal experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals of the University of Tokyo and were approved by the Institutional Animal Care and Use Committee of the University of Tokyo (Permit Number: P12-651).
The primary antibodies from the following sources were used for immunohistochemistry: mouse monoclonal anti-ubiquitin antibody (MAB1510), rabbit polyclonal anti-microtuble-associated protein 2 (MAP2) antibody (AB5622), and rat monoclonal anti-CD11b antibody (MAB1387Z) from Millipore (Billerica, MA, USA); rabbit polyclonal anti-glial fibrillary acidic protein (GFAP) antibody (Z0334) and rabbit polyclonal anti-myelin basic protein (MBP) antibody (A0623) from Dako (Glostrup, Denmark); rabbit polyclonal anti-TDP-43 antibody (10782-2-AP) from Proteintech (Chicago, IL, USA); rabbit polyclonal anti-phospho-TDP-43 (Ser409/410) antibody (TIP-PTD-P02) from CosmoBio (Tokyo, Japan); rabbit polyclonal anti-ionized calcium-binding adapter-1 (Iba1) antibody (019-19741) from Wako chemicals (Osaka, Japan); rat monoclonal anti-CD68 antibody (MCA1957GA) from AbD serotec (Oxford, UK); mouse monoclonal anti-MAP2 antibody (M1406) from Sigma (St. Louis, MO, USA); guinea pig polyclonal anti-p62 antibody (03-GP62-C) from American research products (Waltham, MA, USA); rat monoclonal anti-lysosome associated membrane protein 1 (Lamp1) antibody (553792) from BD pharmingen (Franklin Lakes, NJ, USA). Subsequently, the secondary antibodies from following sources were used: biotin-conjugated goat anti-rabbit IgG antibody and biotin-conjugated goat anti-guinea pig IgG from Vector Laboratories (Burlingame, CA, USA); biotin-conjugated donkey anti-rat IgG from Jackson ImmunoResearch Laboratories (West Grove, PA, USA); Alexa Fluor 488 goat anti-mouse IgG antibody, Alexa Fluor 594 goat anti-mouse IgG antibody, Alexa Fluor 594 goat anti-rabbit IgG antibody, Alexa Fluor 594 goat anti-rat IgG antibody, and Alexa Fluor 488 goat anti-guinea pig IgG antibody from Invitrogen (Carlsbad, CA, USA).
Traumatic brain injury (TBI)
TBI was placed in the cerebral cortex of 10- and 90-week-old WT and KO mice as described previously []. Briefly, mice were anesthetized by intraperitoneal administration of xylazine hydrochloride (8 mg/kg) and chloral hydrate (300 mg/kg) dissolved in sterile saline and subsequently placed in a stereotaxic apparatus (Narishige, Tokyo, Japan). The right cerebral cortex (1.3 mm lateral to the midline, 1 to 3 mm posterior to the bregma, 2 mm in depth) was exposed and injured with a stainless steel cannula with a 0.5-mm outer diameter. Brain samples were taken 4 days after TBI under xylazine hydrochloride and chloral hydrate anesthesia or by decapitation, and all efforts were made to minimize suffering.
Tissue preparation for histological analyses
For immunohistochemical studies, 10- and 90-week-old WT and KO mice (n = 5 for each group) were used. Mice were transcardially perfused with saline followed by 4% paraformaldehyde in PBS (pH 7.2) under xylazine hydrochloride and chloral hydrate anesthesia. Brains were removed from the skull, postfixed in 4% paraformaldehyde overnight, immersed in 10% sucrose in PBS for 24 h, 20% sucrose for 24 h, and 30% sucrose for 48 h for cryoprotection, and cut into 30-μm sections on a cryostat. Sections were preserved in PBS with 0.01% sodium azide. Brain sections from bregma −1.46 to −1.82 were used for the analysis. In the present study, we focused on age-related phenotypical changes in the brain due to PGRN deficiency, and analyzed the uninjured side of the brain unless otherwise mentioned.
Immunochromogenic staining for Iba1, CD68, Lamp1, GFAP, p62, phospho-TDP-43 (pTDP-43) and MBP was carried out on free-floating sections. In brief, sections were incubated in 0.3% hydrogen peroxide for 30 min, blocked in blocking solution (Block Ace, Snow Brand Milk Products, Sapporo, Japan) at room temperature (RT) for 2 h, and exposed to primary antibody (1:500) at 4°C for 60 h. Sections were incubated with biotinylated secondary antibody (1:500) at RT for 2 h, amplified with avidin-biotin complex (Vector Laboratories), and visualized with 3-3′-diaminobenzidine (Sigma) as the chromogen for 1.5 min. All washes were done in 0.03% PBST, incubations with primary and secondary antibodies were done in 0.3% PBST containing 1% BSA, incubations with the avidin-biotin complex were done in 0.3% PBST. Lamp1-, p62-, and pTDP-43-stained sections were counterstained with cresyl violet solution (0.2% cresyl violet, 0.1% acetic acid in distilled water (DW)). Sections were mounted, dehydrated, and coverslipped with Multi Mount 220 (Matsunami Glass, Osaka, Japan). The sections were then observed under a BX-53 microscope equipped with a DP-73 digital microscope camera (Olympus, Tokyo, Japan).
To measure the immunoreactive (IR) areas, the number of pixels per image with an intensity above the predetermined threshold level was quantified, and the total was calculated using NIH ImageJ software (National Institutes of Health, Bethesda, MD, USA) as the percentage area density, which is defined as the number of pixels divided by the total number of pixels in the imaged field. To determine the number of Iba1-IR cells, cells with a clearly outlined, stained soma were counted. Images on the medial and lateral region along the wound site (injured side) and the comparable contralateral side (uninjured side) were used for the analysis of the cerebral cortex. On the other hand, four images of the left VPM/VPL without overlapping were captured and used for the analysis of VPM/VPL, and the values of the four images were averaged. For analysis of the number of Iba1-IR cells in layers IV of the S1BF, an image on the left S1BF was used. A rectangular box (400 × 150 μm) was localized to layers IV of the S1BF, and the number of Iba1-IR cells was counted. To measure fractal dimension (FD) of Iba1-IR cells, ten images of Iba1-IR cells of the left cerebral cortex and VPM/VPL were used for analysis. FD was calculated by the software (PopImaging v5.00, the trial version, http://www.dbkids.co.jp), and the value of the ten images was averaged.
Immunofluorescent staining for MAP2, GFAP, MBP, CD68, p62, ubiquitin, and TDP-43 was carried out on free-floating sections. To improve specific fluorescent signals and reduce autofluorescence, antigen retrieval and Sudan black B treatment was performed as described previously []. Briefly, sections were incubated in 10 mM citrate buffer (pH 6.0) at 90°C for 30 min, followed by incubation in 0.1% Sudan black B (Wako Pure Chemicals) in 70% ethanol for 20 min at RT. The sections were blocked in blocking solution (Block Ace, Snow Brand Milk Products) at RT for 2 h and exposed to primary antibody at 4°C for 60 h. Sections were incubated with Alexa Fluor 488- or 594-conjugated secondary antibody (1:500) at RT for 2 h. Nuclei were stained with Hoechst33258 (0.1 μg/ml; Polysciences Inc., Warrington, PA) at RT for 30 min. All sections were mounted on glass slides and coverslipped with fluoromount (Diagnostic BioSystems, Pleasanton, CA). To analyze the localization of p62, the sections were examined under an LSM 510 laser scanning confocal microscope (Carl Zeiss, Oberkochen, Germany). For triple staining for p62, ubiquitin, and Hoechst33258; p62, TDP-43, and Hoechst33258, the sections were examined under an LSM 5 PASCAL laser scanning confocal microscope (Carl Zeiss).
The left thalamus was dissociated from 90-week-old WT (n = 6) and KO mice (n = 5) using tweezers with a fine tip. Total RNA was isolated from the samples with TRIzol (Invitrogen), and first-strand cDNA was synthesized with SuperScriptII reverse transcriptase (Invitrogen). PCR reactions for cathepsin D (Ctsd), V-type proton ATPase subunit d 2 (Atp6v0d2), transcription factor EB (Tfeb), macrophage expressed gene 1 (Mpeg1), cytochrome b-245 light chain (Cyba), cytochrome b-245 heavy chain (Cybb), complement C4 (C4), tumor necrosis factor α (TNF-α), lipocalin 2 (Lcn2), p62, and hypoxanthine phosphoribosyltransferase (Hprt; an internal standard) were performed with Thunderbird SYBR qPCR MIX (Toyobo, Osaka, Japan), a LightCycler (Roche, Mannheim, Germany), and each primer set listed in Additional file 1: Table S1. The PCR reactions for Hprt were carried out as follows: 1 min at 95°C for the initial denaturation, followed by 40 cycles of amplification at 95°C for 15 s, 67°C for 20 s, and 72°C for 15 s. For other primers, the PCR conditions were: 1 min at 95°C for the initial denaturation, followed by 40 cycles of amplification at 95°C for 15 s and 60°C for 60 s. The genes of interest were normalized to the expression level of Hprt.
Assessment of viable neurons
Viable neurons were visualized using Nissl staining. For Nissl staining, the brain sections were mounted on slides and dried at RT. The slides were incubated with Nissl staining solution (0.2% cresyl violet, 0.1% acetic acid in DW) for 30 min. The slides were washed with DW, dehydrated, and coverslipped with Multi Mount 220 (Matsunami Glass). The sections were then observed under a BX-53 microscope equipped with a DP-73 digital microscope camera (Olympus). For analysis of the number of viable neurons in layers IV, V, and VI of the S1BF, an image on the left S1BF was used. A rectangular box (400 × 150 μm) was localized to layers IV, V, and VI of the S1BF, and the number of viable neurons was counted. For analysis in the VPM/VPL, four images without overlapping were captured, and the number of viable neurons was counted in each image and averaged. A viable neuron was defined as a neuron not exhibiting cytoplasmic shrinkage or nuclear pyknosis.
For autofluorescence analysis, brain sections were mounted on slides, dried at RT, and coverslipped with fluoromount (Diagnostic BioSystems). The sections were then observed under a BX-53 microscope equipped with a DP-73 digital microscope camera (Olympus). The CA3 area was isolated from the hippocampal image using digital image manipulation software (GIMP v2.8.0, Open source software, http://www.gimp.org/) and used for analysis. Four images were captured to avoid overlap with each other on the VPM/VPL. To measure the autofluorescent areas, the number of pixels per image with an intensity above the predetermined threshold level was quantified, and the total was calculated using NIH ImageJ software as the percentage area density, which is defined as the number of pixels divided by the total number of pixels in the imaged field. Further, the brown-yellow pigment in the cytoplasm was evaluated with hematoxylin staining, PAS reactivity after diastase treatment, reducing substances by Schmorl staining, and sudanophilia by Oil-red-O or Sudan black B staining.
Assessment of myelination
Myelination was visualized using avidin-biotin-peroxidase complex method with diaminobenzidine as the chromogen as described in the immunochromogenic staining. The sections were observed under a BX-53 microscope equipped with a DP-73 digital microscope camera (Olympus). To analyze myelination in the temporal association cortex (TeA) and ectorhinal cortex (Ect), an image was captured on the left TeA and Ect, and the image was binarized using digital image manipulation software (GIMP v2.8.0). After that, the distance from the terminal of MBP-IR area to the rim of the cortex in the TeA and Ect was investigated using digital image manipulation software (GIMP v2.8.0).
The data were analyzed with an unpaired t-test or two-way ANOVA followed by a Tukey-Kramer test. Data are expressed as the mean ± SEM. Differences were considered statistically significant when P < 0.05.
PGRN deficiency leads to enhanced CD68 expression in activated microglia
PGRN deficiency leads to an increase in lysosomal biogenesis
PGRN deficiency leads to an increase in astrogliosis
PGRN deficiency results in neuronal loss in the VPM/VPL and increased microgliosis in the S1BF layer IV
PGRN deficiency results in impaired cellular degradation in lysosomes
PGRN deficiency leads to TDP-43 aggregation in the cytoplasm of neurons and lipofuscin accumulation in microglia
PGRN deficiency results in impaired myelination in the cerebral cortex
The present study demonstrated that PGRN deficiency leads to enhanced lysosomal biogenesis in the cerebral cortex and thalamus, especially in the VPM/VPL, with aging. Additionally, we showed impaired lysosomal function and the TDP-43 aggregate in the cytoplasm of neurons in the VPM/VPL in aged PGRN-deficient mice. Further, aged PGRN-deficient mice developed NCL-like pathology. Thus, although the possibility that contusion in the unilateral cerebral cortex might affect the severity of histological changes and the levels of gene expressions in the contralateral cortex and the thalamus could not be ruled out, substantial pathological changes were observed in the aged brain due to PGRN deficiency.
In our previous study, we showed that although the total number of Iba1-IR microglia was not different between WT and KO mice, CD68 immunoreactivity was significantly higher in young (8- or 9-week-old) KO than WT mice that underwent TBI []. In addition, we have shown that PGRN deficiency leads to decreased mammalian target of rapamycin complex 1 (mTORC1) activity with a resultant increase in lysosomal biogenesis in activated microglia after TBI []. Using aged (90-week-old) mice, the present study showed that both the Lamp1 and CD68 immunoreactivity in the cerebral cortex were significantly higher in KO than in WT mice, even in the absence of TBI, whereas the number of Iba1-IR microglia was not different between the two genotypes. Thus, we made similar observations in the TBI and aging models, both of which are associated with microglial activation and microgliosis. PGRN is therefore likely to be primarily implicated in lysosomal biogenesis that leads to microglial activation and microgliosis.
In the present study, we showed that aged PGRN-deficient mice presented with increased accumulation of p62 and ubiquitin in the VPM/VPL, where the main pathological changes have been observed in reported NCL model mice [–]. p62/ubiquitin inclusions have been observed when the autophagy-lysosomal system is disrupted []. Therefore, aged PGRN-deficient mice may have an impaired autophagy-lysosomal system. Since p62 inclusions were observed in neuronal and glial cells, PGRN may play a role in maintaining lysosomal function during aging in both neuronal and glial cells. 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 [], and impaired production of PGRN is involved in this pathology [–]. Previous studies reported increased TDP-43 phosphorylation in PGRN-deficient mice [,,]. 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. Previous studies have shown that abnormal degradation by the autophagy-lysosomal pathway affects TDP-43 aggregation in the cytoplasm [–]. Taken together, these observations suggest that PGRN deficiency may be involved in generating TDP-43 aggregation in the cytoplasm associated with impaired cellular degradation by lysosomes.
We characterized the brain pathology related to NCL in aged PGRN-deficient mice in the present study. PGRN deficiency resulted in neuronal loss, increased gliosis, lipofuscin accumulation in the VPM/VPL, and defective myelination in the cerebral cortex. These pathological changes in aged PGRN-deficient mice are partially consistent with previous studies [,,], though the brain regions examined were different. Analyses using NCL model mice in the previous studies revealed that glial activation precedes neuronal loss in the VPM/VPL [,]. Therefore, the particular vulnerability of the VPM/VPL in PGRN-deficient mice might be attributed to cytotoxicity of glial cells. Since expression of genes for glial cell-derived neurotoxic factors was increased in the VPM/VPL of aged PGRN-deficient mice, PGRN deficiency is likely to make glial cells cytotoxic, thereby leading to enhanced neuroinflammation with aging, though further analysis on the vulnerability of the sensory thalamocortical pathways in PGRN-deficient mice might be needed. In addition, lipofuscin was accumulated in microglia of aged PGRN-deficient mice. Lipofuscin is thought to be an end product of cellular protein metabolism, especially protein catabolism []. Since macrophage in PGRN-deficient mice displayed enhanced rates of apoptotic-cell phagocytosis [], microglia in PGRN-deficient mice might be more phagocytically active and thereby overloaded with waste products with a resultant increase in lipofuscin deposits. In the present study, defective myelination and enhanced astrogliosis occurred in the cerebral cortex of aged PGRN-deficient mice, but neuronal loss was not observed in the cerebral cortex. Similar observations were also made in 3-month-old mice lacking Cln1, a mutation in which causes classic infantile NCL []. Because astrocytes are implicated in myelination in the brain [,], PGRN deficiency might lead to impaired astrocyte function and consequently induce defective myelination, though further studies are necessary to elucidate myelination deficits due to PGRN deficiency. These observations indicate that our PGRN-deficient mice may be another useful experimental model for NCL.
Recently, it is reported that PGRN-deficient mice recapitulate pathobiomedical features of NCL and FTLD, e.g. increased lysosomal proteins and TDP-43 phosphorylation, and that FTLD patients due to PGRN deficiency have NCL-like pathology []. The present study also revealed that aged PGRN-deficient mice have characteristic features for both FTLD and NCL. Since lysosomal functions are involved in the pathogenesis of these diseases [,,], increased lysosomal biogenesis and lysosomal dysfunction as observed in PGRN-deficient mice in the present study may be common processes in the pathogenic mechanism of these diseases. We have previously suggested that PGRN is localized in lysosomes and may be involved in the activation of mTORC1, which prevents translocation of TFEB to the nucleus by phosphorylation, thereby decreasing lysosomal biogenesis []. Further studies on the molecular mechanism underlying the actions of PGRN are needed to elucidate pathophysiological changes of the aged brain due to PGRN deficiency.
The present study demonstrated that aged PGRN-deficient mice show exacerbated neuronal loss, lipofuscin accumulation, gliosis, and increased lysosomal protein and gene expressions in the VPM/VPL of the thalamus, suggesting that aged PGRN-deficient mice develop NCL-like pathology. In addition, the presence of p62 aggregates in the VPM/VPL of aged PGRN-deficient mice suggests that TDP-43 aggregates observed in the cytoplasm of neurons in this brain region are associated with impaired cellular degradation by lysosomal dysfunction. To our knowledge, this is the first report showing NCL-like pathology and TDP-43 aggregates in the VPM/VPL of aged PGRN-deficient mice. Clarifying the mechanisms by which PGRN regulates lysosomal function may be crucial to elucidate pathoetiology of brain disorders resulting from PGRN deficiency.
YT is a JSPS postdoctoral research fellow, Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science. JKC is an assistant Professor, Department of Veterinary Pathology, The University of Tokyo. TM is an assistant Professor, Department of Veterinary Physiology, The University of Tokyo. KY is an associate Professor, Department of Veterinary Physiology, The University of Tokyo. MN is a Professor, Department of Veterinary Physiology, The University of Tokyo.
Frontotemporal lobar degeneration
Neuronal ceroid lipofuscinosis
Ventral posteromedial nucleus/ventral posterolateral nucleus
TAR DNA binding protein 43
Phospho-TAR DNA binding protein 43
Traumatic brain injury
Primary somatosensory barrelfield cortex
PBS containing Triton X-100
Temporal association cortex
Mammalian target of rapamycin complex 1
We are grateful to Sei Sato, Kazunori Sato, and Atsuhiro Tsutiya in the Graduate School of Life Sciences, Toyo University, Japan for technical help using the confocal microscope. This work was supported in part by JSPS KAKENHI Grant Number 23228004 to MN and 24-7548 to YT.
- Cenik B, Sephton CF, Kutluk Cenik B, Herz J, Yu G: Progranulin: a proteolytically processed protein at the crossroads of inflammation and neurodegeneration. J Biol Chem 2012, 287: 32298–32306. 10.1074/jbc.R112.399170View ArticlePubMedPubMed CentralGoogle Scholar
- Bateman A, Bennett HP: The granulin gene family: from cancer to dementia. Bioessays 2009, 31: 1245–1254. 10.1002/bies.200900086View ArticlePubMedGoogle Scholar
- Thurner L, Preuss KD, Fadle N, Regitz E, Klemm P, Zaks M, Kemele M, Hasenfus A, Csernok E, Gross WL, Pasquali JL, Martin T, Bohle RM, Pfreundschuh M: Progranulin antibodies in autoimmune diseases. J Autoimmun 2013, 42: 29–38. 10.1016/j.jaut.2012.10.003View ArticlePubMedGoogle Scholar
- Matsubara T, Mita A, Minami K, Hosooka T, Kitazawa S, Takahashi K, Tamori Y, Yokoi N, Watanabe M, Matsuo E, Nishimura O, Seino S: PGRN is a key adipokine mediating high fat diet-induced insulin resistanceand obesity through IL-6 in adipose tissue. Cell Metab 2012, 15: 38–50. 10.1016/j.cmet.2011.12.002View ArticlePubMedGoogle Scholar
- Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M: Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006, 442: 916–919. 10.1038/nature05016View ArticlePubMedGoogle Scholar
- Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ, van Duijn C, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, Van den Broeck M, Cuijt I, Vennekens K, De Deyn PP, Kumar-Singh S, Van Broeckhoven C: Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 2006, 442: 920–924. 10.1038/nature05017View ArticlePubMedGoogle Scholar
- Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T: TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 2006, 351: 602–611. 10.1016/j.bbrc.2006.10.093View ArticlePubMedGoogle Scholar
- Tanaka Y, Matsuwaki T, Yamanouchi K, Nishihara M: Exacerbated inflammatory responses related to activated microglia after traumatic brain injury in progranulin-deficient mice. Neuroscience 2013, 231: 49–60. 10.1016/j.neuroscience.2012.11.032View ArticlePubMedGoogle Scholar
- Tanaka Y, Matsuwaki T, Yamanouchi K, Nishihara M: Increased lysosomal biogenesis in activated microglia and exacerbated neuronal damage after traumatic brain injury in progranulin-deficient mice. Neuroscience 2013, 250: 8–19. 10.1016/j.neuroscience.2013.06.049View ArticlePubMedGoogle Scholar
- Conde JR, Streit WJ: Microglia in the aging brain. J Neuropathol Exp Neurol 2006, 65: 199–203. 10.1097/01.jnen.0000202887.22082.63View ArticlePubMedGoogle Scholar
- Wils H, Kleinberger G, Pereson S, Janssens J, Capell A, Van Dam D, Cuijt I, Joris G, De Deyn PP, Haass C, Van Broeckhoven C, Kumar-Singh S: Cellular ageing, increased mortality and FTLD-TDP-associated neuropathology in progranulin knockout mice. J Pathol 2012, 228: 67–76.PubMedGoogle Scholar
- Smith KR, Damiano J, Franceschetti S, Carpenter S, Canafoglia L, Morbin M, Rossi G, Pareyson D, Mole SE, Staropoli JF, Sims KB, Lewis J, Lin WL, Dickson DW, Dahl HH, Bahlo M, Berkovic SF: Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. Am J Hum Genet 2012, 90: 1102–1107. 10.1016/j.ajhg.2012.04.021View ArticlePubMedPubMed CentralGoogle Scholar
- Götzl JK, Damme M, Fellerer K, Tahirovic S, Kleinberger G, Janssens J, Van Der Zee J, Lang CM, Kremmer E, Martin JJ, Engelborghs S, Kretzschmar HA, Arzberger T, Van Broeckhoven C, Haass C, Capell A: Common pathobiochemical hallmarks of progranulin-associated frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis. Acta Neuropathol 2014. in press.
- Jalanko A, Braulke T: Neuronal ceroid lipofuscinoses. Biochim Biophys Acta 2009, 1793: 697–709. 10.1016/j.bbamcr.2008.11.004View ArticlePubMedGoogle Scholar
- Cooper JD: The neuronal ceroid lipofuscinoses: the same, but different? Biochem Soc Trans 2010, 38: 1448–1452. 10.1042/BST0381448View ArticlePubMedGoogle Scholar
- Kielar C, Maddox L, Bible E, Pontikis CC, Macauley SL, Griffey MA, Wong M, Sands MS, Cooper JD: Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis. Neurobiol Dis 2007, 25: 150–162. 10.1016/j.nbd.2006.09.001View ArticlePubMedGoogle Scholar
- Partanen S, Haapanen A, Kielar C, Pontikis C, Alexander N, Inkinen T, Saftig P, Gillingwater TH, Cooper JD, Tyynelä J: Synaptic changes in the thalamocortical system of cathepsin D-deficient mice: a model of human congenital neuronal ceroid-lipofuscinosis. J Neuropathol Exp Neurol 2008, 67: 16–29. 10.1097/nen.0b013e31815f3899View ArticlePubMedGoogle Scholar
- von Schantz C, Kielar C, Hansen SN, Pontikis CC, Alexander NA, Kopra O, Jalanko A, Cooper JD: Progressive thalamocortical neuron loss in Cln5 deficient mice: Distinct effects in Finnish variant late infantile NCL. Neurobiol Dis 2009, 34: 308–319. 10.1016/j.nbd.2009.02.001View ArticlePubMedPubMed CentralGoogle Scholar
- Blom T, Schmiedt ML, Wong AM, Kyttälä A, Soronen J, Jauhiainen M, Tyynelä J, Cooper JD, Jalanko A: Exacerbated neuronal ceroid lipofuscinosis phenotype in Cln1/5 double-knockout mice. Dis Model Mech 2013, 6: 342–357. 10.1242/dmm.010140View ArticlePubMedGoogle Scholar
- Kuronen M, Hermansson M, Manninen O, Zech I, Talvitie M, Laitinen T, Gröhn O, Somerharju P, Eckhardt M, Cooper JD, Lehesjoki AE, Lahtinen U, Kopra O: Galactolipid deficiency in the early pathogenesis of neuronal ceroid lipofuscinosis model Cln8 mnd : implications to delayed myelination and oligodendrocyte maturation. Neuropathol Appl Neurobiol 2012, 38: 471–486. 10.1111/j.1365-2990.2011.01233.xView ArticlePubMedGoogle Scholar
- Kayasuga Y, Chiba S, Suzuki M, Kikusui T, Matsuwaki T, Yamanouchi K, Kotaki H, Horai R, Iwakura Y, Nishihara M: Alteration of behavioural phenotype in mice by targeted disruption of the progranulin gene. Behav Brain Res 2007, 185: 110–118. 10.1016/j.bbr.2007.07.020View ArticlePubMedGoogle Scholar
- Oliveira VC, Carrara RC, Simoes DL, Saggioro FP, Carlotti CG Jr, Covas DT, Neder L: Sudan Black B treatment reduces autofluorescence and improves resolution of in situ hybridization specific fluorescent signals of brain sections. Histol Histopathol 2010, 25: 1017–1024.PubMedGoogle Scholar
- Sofroniew MV, Vinters HV: Astrocytes: biology and pathology. Acta Neuropathol 2010, 119: 7–35. 10.1007/s00401-009-0619-8View ArticlePubMedGoogle Scholar
- Boellaard JW, Schlote W, Hofer W: Species-specific ultrastructure of neuronal lipofuscin in hippocampus and neocortex of subhuman mammals and humans. Ultrastruct Pathol 2004, 28: 341–351. 10.1080/019131290882330View ArticlePubMedGoogle Scholar
- Boggs JM: Myelin basic protein: a multifunctional protein. Cell Mol Life Sci 2006, 63: 1945–1961. 10.1007/s00018-006-6094-7View ArticlePubMedGoogle Scholar
- Ferguson CJ, Lenk GM, Meisler MH: Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2. Hum Mol Genet 2009, 18: 4868–4878. 10.1093/hmg/ddp460View ArticlePubMedPubMed CentralGoogle Scholar
- Ju JS, Weihl CC: Inclusion body myopathy, Paget’s disease of the bone and fronto-temporal dementia: a disorder of autophagy. Hum Mol Genet 2010, 19: R38-R45. 10.1093/hmg/ddq157View ArticlePubMedPubMed CentralGoogle Scholar
- Yin F, Dumont M, Banerjee R, Ma Y, Li H, Lin MT, Beal MF, Nathan C, Thomas B, Ding A: Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementia. FASEB J 2010, 24: 4639–4647. 10.1096/fj.10-161471View ArticlePubMedPubMed CentralGoogle Scholar
- Filimonenko M, Stuffers S, Raiborg C, Yamamoto A, Malerød L, Fisher EM, Isaacs A, Brech A, Stenmark H, Simonsen A: Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. J Cell Biol 2007, 179: 485–500. 10.1083/jcb.200702115View ArticlePubMedPubMed CentralGoogle Scholar
- Wang X, Fan H, Ying Z, Li B, Wang H, Wang G: Degradation of TDP-43 and its pathogenic form by autophagy and the ubiquitin-proteasome system. Neurosci Lett 2010, 469: 112–116. 10.1016/j.neulet.2009.11.055View ArticlePubMedGoogle Scholar
- Caccamo A, Majumder S, Deng JJ, Bai Y, Thornton FB, Oddo S: Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability. J Biol Chem 2009, 284: 27416–27424. 10.1074/jbc.M109.031278View ArticlePubMedPubMed CentralGoogle Scholar
- Gomes C, Escrevente C, Costa J: Mutant superoxide dismutase 1 overexpression in NSC-34 cells: effect of trehalose on aggregation, TDP-43 localization and levels of co-expressed glycoproteins. Neurosci Lett 2010, 475: 145–149. 10.1016/j.neulet.2010.03.065View ArticlePubMedGoogle Scholar
- Ahmed Z, Sheng H, Xu YF, Lin WL, Innes AE, Gass J, Yu X, Wuertzer CA, Hou H, Chiba S, Yamanouchi K, Leissring M, Petrucelli L, Nishihara M, Hutton ML, McGowan E, Dickson DW, Lewis J: Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging. Am J Pathol 2010, 177: 311–324. 10.2353/ajpath.2010.090915View ArticlePubMedPubMed CentralGoogle Scholar
- Kuronen M, Lehesjoki AE, Jalanko A, Cooper JD, Kopra O: Selective spatiotemporal patterns of glial activation and neuron loss in the sensory thalamocortical pathways of neuronal ceroid lipofuscinosis 8 mice. Neurobiol Dis 2012, 47: 444–457. 10.1016/j.nbd.2012.04.018View ArticlePubMedGoogle Scholar
- Kao AW, Eisenhut RJ, Martens LH, Nakamura A, Huang A, Bagley JA, Zhou P, de Luis A, Neukomm LJ, Cabello J, Farese RV Jr, Kenyon C: A neurodegenerative disease mutation that accelerates the clearance of apoptotic cells. Proc Natl Acad Sci U S A 2011, 108: 4441–4446. 10.1073/pnas.1100650108View ArticlePubMedPubMed CentralGoogle Scholar
- Schulz K, Kroner A, David S: Iron efflux from astrocytes plays a role in remyelination. J Neurosci 2012, 32: 4841–4847. 10.1523/JNEUROSCI.5328-11.2012View ArticlePubMedGoogle Scholar
- Barateiro A, Domingues HS, Fernandes A, Relvas JB, Brites D: Rat cerebellar slice cultures exposed to bilirubin evidence reactive gliosis, excitotoxicity and impaired myelinogenesis that is prevented by AMPA and TNF-α inhibitors. Mol Neurobiol 2014, 49: 424–439. 10.1007/s12035-013-8530-7View ArticlePubMedGoogle Scholar
- Appelqvist H, Wäster P, Kågedal K, Ollinger K: The lysosome: from waste bag to potential therapeutic target. J Mol Cell Biol 2013, 5: 214–226. 10.1093/jmcb/mjt022View ArticlePubMedGoogle Scholar
- Brady OA, Zheng Y, Murphy K, Huang M, Hu F: The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function. Hum Mol Genet 2013, 22: 685–695. 10.1093/hmg/dds475View ArticlePubMedGoogle Scholar
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