Elevated TMEM106B levels exaggerate lipofuscin accumulation and lysosomal dysfunction in aged mice with progranulin deficiency
- Xiaolai Zhou†1,
- Lirong Sun†1, 2,
- Owen Adam Brady1,
- Kira A. Murphy1 and
- Fenghua Hu1Email authorView ORCID ID profile
© The Author(s). 2017
Received: 21 December 2016
Accepted: 14 January 2017
Published: 26 January 2017
Mutations resulting in haploinsufficiency of progranulin (PGRN) cause frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP), a devastating neurodegenerative disease. Accumulating evidence suggest a crucial role of progranulin in maintaining proper lysosomal function during aging. TMEM106B has been identified as a risk factor for frontotemporal lobar degeneration with progranulin mutations and elevated mRNA and protein levels of TMEM106B are associated with increased risk for frontotemporal lobar degeneration. Increased levels of TMEM106B alter lysosomal morphology and interfere with lysosomal degradation. However, how progranulin and TMEM106B interact to regulate lysosomal function and frontotemporal lobar degeneration (FTLD) disease progression is still unclear. Here we report that progranulin deficiency leads to increased TMEM106B protein levels in the mouse cortex with aging. To mimic elevated levels of TMEM106B in frontotemporal lobar degeneration (FTLD) cases, we generated transgenic mice expressing TMEM106B under the neuronal specific promoter, CamKII. Surprisingly, we found that the total protein levels of TMEM106B are not altered despite the expression of the TMEM106B transgene at mRNA and protein levels, suggesting a tight regulation of TMEM106B protein levels in the mouse brain. However, progranulin deficiency results in accumulation of TMEM106B protein from the transgene expression during aging, which is accompanied by exaggerated lysosomal abnormalities and increased lipofuscin accumulation. In summary, our mouse model nicely recapitulates the interaction between progranulin and TMEM106B in human patients and supports a critical role of lysosomal dysfunction in the frontotemporal lobar degeneration (FTLD) disease progression.
Frontotemporal lobar degeneration (FTLD) is a devastating neurodegenerative disease that affects approximately 250,000 people in the United States [24, 28]. Clinical symptoms of FTLD include behavioral abnormalities, personality changes, and language impairments . A major type of FTLD shows TDP-43 and ubiquitin positive inclusions (FTLD-TDP) [3, 26]. Progranulin (PGRN) haploinsufficiency due to mutations in the Progranulin gene (GRN) is one of the major causes of FTLD-TDP [4, 11, 17].
Additional environmental or genetic factors influence the manifestation of FTLD-TDP, resulting in a high variability in age of onset and pathological presentation, even with identical mutations . Recent genome-wide association studies by several groups have identified TMEM106B, a gene encoding a type II transmembrane protein of unknown function, as a bona fide risk factor for FTLD-TDP, especially in patients with PGRN mutations [10, 13, 15, 41, 43]. The TMEM106B risk allele was reported to increase TMEM106B mRNA levels . Both mRNA and protein levels of TMEM106B are elevated in FTLD-TDP patients, especially in PGRN mutant carriers . These data suggest that PGRN might regulate TMEM106B protein homeostasis and elevated TMEM106B levels increase the risk for FTLD-TDP with PGRN mutations.
Our recent studies and others showed that TMEM106B is highly expressed in neurons, mainly localizes in the late endosome/lysosome compartments, and regulates lysosomal morphology [6, 7, 20, 21, 36]. Overexpression of TMEM106B results in accumulation of enlarged lysosomes and delays the degradation of endocytic cargoes, such as EGFR . More recently, TMEM106B was shown to interact with MAP6 to control lysosomal trafficking in dendrites and decreased levels of TMEM106B result in defects in lysosome size, mobility and lysosomal trafficking in neurons [33, 36]. These observations strongly argue that proper regulation of TMEM106B levels is critical for normal lysosomal function and that impaired lysosomal function due to elevated TMEM106B levels might accelerate the development of FTLD phenotypes. Along this line, several recent studies have suggested a critical role of PGRN in lysosomes. Human patients with a total loss of PGRN exhibit neuronal ceroid lipofuscinosis (NCL) , a lysosomal storage disease characterized by the accumulation of auto-fluorescent storage material (lipofuscin). NCL phenotypes and lysosomal abnormalities were also seen in PGRN knockout mice [1, 18, 38]. Furthermore, PGRN is transcriptionally co-regulated with a number of essential lysosomal genes , and we have demonstrated that PGRN is a lysosomal resident protein delivered to lysosomes through two independent mechanisms [19, 46]. Finally, FTLD-TDP/PGRN patients also exhibit typical pathological features of NCL pathology , suggesting FTLD and NCL caused by PGRN mutations are pathologically linked. Thus the identification of TMEM106B as a risk factor for FTLD with PGRN mutations and the fact that increased TMEM106B levels impair lysosomal function further underscore lysosomal dysfunction as one of the disease mechanisms for FTLD.
To determine an in vivo effect of elevated TMEM106B levels in mouse models, we generated transgenic lines expressing human TMEM106B under a neuronal specific promoter. To our surprise, we found that TMEM106B protein levels are tightly regulated despite the expression of the transgene at RNA and protein level. However, elevated TMEM106B levels were detected in aged PGRN deficient mice expressing the transgene, which exacerbates the lysosomal abnormality and lipofuscin accumulation in the PGRN deficient background. Thus our data nicely illustrates the cross-regulation between PGRN and TMEM106B during aging and neurodegeneration.
Pharmacological reagents and antibodies
The following antibodies were used in this study: rat anti-mouse LAMP1 (1D4B) from BD Biosciences, goat anti-mouse Cathepsin D (C-20) from Santa Cruz and mouse anti-beta III tubulin from Promega. Rabbit anti-subunit c of mitochondrial ATP synthase (SCMAS) antibodies  were a gift from Dr. Elizabeth F. Neufeld (David Geffen School of Medicine, University of California, Los Angeles, CA). Rabbit anti-TMEM106B antibodies were generated against the cytosolic domain of human TMEM106B as previously described .
Human TMEM106B cDNAs with polyA sequence from the pEGFP-C1 vector were amplified and cloned into the pMM403 plasmid from Addgene (plasmid 34926) using the NotI restriction site. The expression cassette was excised by digestion with the restriction enzyme SfiI and injected into the pronuclei of fertilized eggs derived from FVB/NJ strain by the Transgenic Mouse Facility at Cornell University to yield offspring with different expression levels of TMEM106B. 16 pups were born after one round of injection and implantation. The founder #2 with the highest TMEM106B was selected and back crossed with wild type C57/BL6 for three generation for experimental analysis. Wild type C57/BL6 and PGRN−/− mice were obtained from Jackson Laboratories. All mice were housed in the Weill Hall animal facility.
Genomic DNA was extracted from mouse tails using the REDextract kit from Sigma. Primers with sequences 5’TCCAACCCCCTCAGTACATC3’ and 5’TTTTCTTGCCCCCTAGGAAT3’ were used to identify human TMEM106B transgene (594 bp PCR product). Notch primers (5’ GATATC GTGGTGCATACCCTCCTG3’ and 5’ GTGGTCTAGGATGCTTGGGTCTAG 3’) were used to amplify Notch1 as an internal control (300 bp PCR product). Progranulin deficient mice were genotyped using the mixture of following primers: 5’ AGAGGGTGAGCTGCAATGTT 3’, 5’AAGGGCATTAGCCAAGTGTG3’ and 5’TCTCCCAGGTAGCCCCTACT3’ in which wild type has a 468 bp product and PGRN−/− has a 211 bp PCR product.
Western blot analysis
Cortices were homogenized in RIPA buffer on ice and an equal volume of 2X SDS sample buffer was added before sonication. Samples were maintained on ice throughout before loading on SDS-PAGE. TMEM106B protein runs as a dimer under this condition (Additional file 1) . Western blots were done as previously described . TMEM106B protein levels were quantified using LiCor Odyssey system and normalized to beta III tubulin.
mRNAs were extracted from cortices using TRIZOL (Invitrogen). mRNAs were reversed transcribed to cDNAs using iScript kit (Biorad). Real time PCRs were done on Roche Lifecycler 480 using the following primers: mouse actin (5’ACGAGGCCCAGAGCAAGAG3’ and 5’TCTCCAAGTCGTCCCAGTTG3’), mouse TMEM106B 5’CGCGTGCGGTTTCTAGAGCAT 3’ and 5’CCTCCCCGGGCTCTCAATGT3’) and human TMEM106B (5’GGGCAAGAAAACCAACTGGTGGC3’ and 5’ TCACGTCGATAGAGCGAGGGAA 3’). All the primers have the amplification efficiency close to 100%. Transcript levels were calculated using efficiency-adjusted ΔΔ-CT. All transcripts were normalized to actin.
Mass spectrometry analysis
Cortices were dissected from TMEM106B transgenic mice at 1.5 months old and lysed in 50 mM Tris, 150 mM NaCl and 1% Triton plus protease inhibitors (Roche). After centrifugation, the supernatant was immunoprecipitated with Affigel (Biorad) conjugated with anti-TMEM106B antibodies. 2% of the IP products were eluted, trypsinized and analyzed by mass spec as previously described [19, 46].
Mouse brains were perfused and fixed with 4% formaldehyde. After gradient dehydration with 15% and 30% sucrose, the mouse brains were embedded with OCT compound (Sakura Finetek USA) and sliced with Cryotome. For immunostaining (not for lipofuscin analysis), brain sections were incubated with 0.01% Sudan Black B (Spectrum Chemical) in 70% ethanol at room temperature for 20 min to negate the autofluorescence, then permeabilized and blocked in blocking buffer (0.05% saponin, 3% BSA in TBS) for 1 h. Primary antibodies were incubated in blocking buffer overnight at 4 °C. Sections were washed and incubated in secondary antibodies conjugated to Alexaflour 488, 568, or 660 (Invitrogen). Sections were washed three more times and coverslips mounted onto slides with Fluoromount G (Southern Biotech). Images were acquired on a CSU-X spinning disc confocal microscope (Intelligent Imaging Innovations) with an HQ2 CCD camera (Photometrics) using a 40x or 100x objective.
Quantification of enlarged lysosomes and lipofuscin
For the quantification of enlarged lysosomes, the lysosomes were visualized by anti-LAMP1 staining, and the entire neuron somas were captured using Z stack. Neurons with enlarged lysosomes (diameter > 1.0 μm) were counted. It should be noted that during fixation, lysosomal size and area might have been changed but we always have a control group and experimental group analyzed at the same time. For lipofuscin analysis, brain sections were stained with Hochest 33324 solution (Thermo Fisher Scientific) after permeabilization and blocking. Images were acquired on an epifluorescence microscope (Zeiss) equipped with a CCD camera. Auto fluorescent signals were quantified using Image J (NIH).
The data were presented as mean ± SEM. Statistical significance between multiple groups was analyzed by one-way ANOVA followed by Bonferroni’s multiple comparison test. Two-group analysis was performed using the Student’s t test. P-values <0.05 were considered statistically significant. All statistical analyses were performed using GraphPad Prism 5 software (GraphPad Software).
Generation of TMEM106B transgenic mice
Tight regulation of TMEM106B protein levels in the transgenic line
Progranulin deficiency leads to increased TMEM106B levels in the aged mice
Expression of TMEM106B transgene exacerbates lysosomal abnormalities of PGRN deficient mice
In this study we generated transgenic mice expressing human TMEM106B cDNA under the neuronal specific promoter CamKII. The expression of human transgene was confirmed by qPCR at the RNA level and by mass spectrometry analysis at the protein level. However, despite the expression of the transgene, the total protein level of TMEM106B in the cortex of the young mice is not changed, suggesting a tight regulation of TMEM106B protein levels in neurons. Our data further showed that PGRN is one of the key mechanisms that promotes TMEM106B turnover in the aged brain.
Multiple studies have suggested a critical role of TMEM106B in regulating lysosomal function [6, 7, 20, 21, 36] and elevated TMEM106B levels are associated with increased risk for FTLD-TDP with PGRN mutations [10, 15, 41, 43]. Since proper lysosomal function is critical towards preventing neurodegeneration, it is not surprising that TMEM106B levels are tightly regulated to ensure proper lysosomal activities. Indeed, TMEM106B protein is a substrate for lysosomal degradation [6, 7, 21]. Thus healthy lysosomes are able to maintain proper TMEM106B levels through their own degradative activities.
Loss of PGRN results in NCL in humans  and increased accumulation of lipofuscin in mice during aging [1, 38]. We also demonstrated that PGRN is a lysosomal resident protein [19, 46]. However, the precise function of PGRN in the lysosome is still unknown. Our data support that at least one function of PGRN is to promote TMEM106B degradation to maintain the proper level of TMEM106B on lysosomal membranes in the aged brain. How PGRN performs this action, though, remains unknown. One possibility is that PGRN helps maintain the proper activity of lysosomal enzymes during aging. In addition to TMEM106B, other lysosomal substrates accumulate in response to PGRN deficiency. SCMAS and saposin D, components of the lipofuscin, aggregate in PGRN−/− mouse brain and FTLD-PGRN patient samples (Fig. 6) . It remains to be determined whether PGRN plays a direct role in TMEM106B turnover or indirectly by regulating lysosomal functions.
TDP-43 aggregation and hyper-phosphorylation is a hallmark for FTLD with PGRN mutations [4, 11, 17]. However, we failed to detect TDP-43 pathology in our PGRN deficient mice with or without TMEM106B transgene overexpression (data not shown). Thus the FTLD pathology is not fully recapitulated in mouse models.
A portion of FTLD patients also develop amyotrophic lateral sclerosis (ALS) phenotypes (FTLD/ALS). Hexanucleotide repeat expansion in the intron region of the C9orf72 gene, are responsible for the majority cases of FTLD/ALS with TDP-43 aggregates [12, 30, 44]. Recently TMEM106B polymorphisms have been shown to modify the disease phenotypes in FTLD/ALS cases with repeat expansions in the C9orf72 gene [16, 22, 40]. C9orf72 might also be involved in endolysosomal trafficking and autophagy-lysosome pathway [2, 8, 14, 27, 34, 37, 39, 45]. TMEM106B is also implicated in pathological presentation of Alzheimer’s disease  and lysosomal dysfunction has been shown to be implicated in Alzheimer’s disease as well. Thus it will be interesting to investigate whether lysosomal impairment in FTLD/ALS/C9orf72 and AD cases could trigger the imbalance in TMEM106B protein homeostasis that leads to TMEM106B induced toxicity.
Our TMEM106B transgenic mouse model nicely recapitulates the interaction between progranulin and TMEM106B in human patients and support a regulation of TMEM106B by progranulin in the aged brain and a role of TMEM106B in FTLD-PGRN disease progression.
We thank Dr. Francisco Bastos de Oliveira and Dr. Marcus Smolka for mass spec analysis; Dr. Elizabeth Neufeld (UCLA) for anti-SCMAS antibodies; and Mr. Robert Fragoza for proofreading the manuscript. This work is supported by funding to F.H. from the Weill Institute for Cell and Molecular Biology, the Alzheimer’s Association, the Association of Frontotemporal Dementia (AFTD), the Muscular Dystrophy Association and NINDS (R21 NS081357-01, R01NS088448-01) and by funding to X. Z. from the Weill Institute Fleming Postdoctoral Fellowship.
This work is supported by NINDS (R21 NS081357-01, R01NS088448-01) to F.H. X. Z. is supported by the Weill Institute Fleming Postdoctoral Fellowship.
FH conceived and supervised the project. FH and XZ analyzed the data and wrote the manuscript. XZ characterized TMEM106B protein level changes and NCL and lysosomal phenotypes. LS performed qPCR and helped with mouse work and Western blot analysis; FH designed and generated the transgenic construct; OAB helped qPCR analysis and KAM helped with mouse genotyping. All authors read and approved the manuscript.
The authors declare that they have no competing interests.
Ethics approval and consent to participate
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. The work under animal protocol 2014–0071 is approved by the Institutional Animal Care and Use Committee at Cornell University.
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