Acta Neuropathologica

, Volume 124, Issue 2, pp 231–245 | Cite as

TDP-43 regulates the mammalian spinogenesis through translational repression of Rac1

  • Pritha Majumder
  • Yi-Ting Chen
  • Jayarama Krishnan Bose
  • Cheng-Chun Wu
  • Wei-Cheng Cheng
  • Sin-Jhong Cheng
  • Yen-Hsin Fang
  • Ying-Ling Chen
  • Kuen-Jer Tsai
  • Cheng-Chang Lien
  • Che-Kun James Shen
Original Paper

Abstract

Impairment of learning and memory is a significant pathological feature of many neurodegenerative diseases including FTLD-TDP. Appropriate regulation and fine tuning of spinogenesis of the dendrites, which is an integral part of the learning/memory program of the mammalian brain, are essential for the normal function of the hippocampal neurons. TDP-43 is a nucleic acid-binding protein implicated in multi-cellular functions and in the pathogenesis of a range of neurodegenerative diseases including FTLD-TDP and ALS. We have combined the use of single-cell dye injection, shRNA knockdown, plasmid rescue, immunofluorescence staining, Western blot analysis and patch clamp electrophysiological measurement of primary mouse hippocampal neurons in culture to study the functional role of TDP-43 in mammalian spinogenesis. We found that depletion of TDP-43 leads to an increase in the number of protrusions/spines as well as the percentage of matured spines among the protrusions. Significantly, the knockdown of TDP-43 also increases the level of Rac1 and its activated form GTP-Rac1, a known positive regulator of spinogenesis. Clustering of the AMPA receptors on the dendritic surface and neuronal firing are also induced by depletion of TDP-43. Furthermore, use of an inhibitor of Rac1 activation negatively regulated spinogenesis of control hippocampal neurons as well as TDP-43-depleted hippocampal neurons. Mechanistically, RT-PCR assay and cycloheximide chase experiments have indicated that increases in Rac1 protein upon TDP-43 depletion is regulated at the translational level. These data together establish that TDP-43 is an upstream regulator of spinogenesis in part through its action on the Rac1 → GTP-Rac1 → AMPAR pathway. This study provides the first evidence connecting TDP-43 with the GTP-Rac1 → AMPAR regulatory pathway of spinogenesis. It establishes that mis-metabolism of TDP-43, as occurs in neurodegenerative diseases with TDP-43 proteinopathies, e.g., FTLD-TDP, would alter its homeostatic cellular concentration, thus leading to impairment of hippocampal plasticity.

Keywords

TDP-43 FTLD-TDP Tg mouse model Spinogenesis GTP-Rac1 GluR1 Translation 

Abbreviations

ALS

Amyotrophic lateral sclerosis

AMPAR

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

CamKII

Calmodulin-dependent protein kinase I

DIV

Day in vitro

dTDP

Drosophila TDP-43

FTLD-U

Frontotemporal lobar degeneration with ubiquitin-positive inclusions

GTP

Guanosine-5¢-triphosphate

mEPSC

Miniature excitatory postsynaptic current

TDP-43

TAR DNA-binding protein-43

Notes

Acknowledgments

We thank Lien-Szu Wu and Dr. Yi-Ping Hsueh’s laboratory members, in particular Hsiao-Tang Hu, for their technical and conceptual advice on the culturing and DNA transfection of mouse hippocampal neurons. We also thank Drs. Ruey-Hwa Chen (IBC, Academia Sinica) and Zee-Fen Chang (National Yang-Ming University), and the late Dr. Hung-Li (IMB, Academia Sinica) for their generous gifts of material used in this study. The expertise of Ms. Huei-Fang Wu in the Electrophysiology Core, NPAS, Academia Sinica, and Sue-Ping Lee/Shu-Mei Huang in the Microscopy Core at IMB are also greatly appreciated. We sincerely convey our gratitude to Dr. Guo-Jen Huang (Chang Gung University) for his help on the Golgi staining experiments. This work was supported by the Frontier of Science Award from the National Science Council and an Investigator Award from the Academia Sinica, Taipei, Taiwan.

Supplementary material

401_2012_1006_MOESM1_ESM.doc (50 kb)
Supplementary material 1 (DOC 50 kb)
401_2012_1006_MOESM2_ESM.tif (2.4 mb)
Figure S1. The effect of TDP-43 over-expression on the morphogenesis of cultured hippocampal neurons (a) Analysis of hippocampal neurons with micro-injection of biocytin. (I) Hippocampal neurons from wild type (Wt) and CamKII-TDP-43 Tg mice (Tg) under bright field microscope before the micro-injection (control, the upper 4 panels) and under fluorescence microscope after micro-injection of biocytin followed by staining with Avidin-conjugated Alexa 488 (dye injection, the lower 4 panels). The scale bar is 10 µm. The bar diagrams show the comparisons of the total neurite length per neuron (II), the branch number per neuron (III), and the major shaft number per neuron (IV), at DIV 7, 14, and 21 for each group. 18-19 neurons were scored in each case and there was no significant difference between the Wt and Tg samples (p>0.05). (b) Comparison of the dendritic protrusion densities of Wt and TDP-43 Tg hippocampal neurons in culture at DIV 7, 14, and 21. Images of the neurites taken from DeltaVision image stacks are exemplified on the left, with the yellow arrowheads pointing to the protrusions. The bar diagram shows the means of the dendritic protrusion densities at DIV 7, 14 and 21 for each group. The error bars represent the standard deviations (SE). ** and *** indicate significant decreases of the protrusion densities of the Tg hippocampal neurons at DIV 14 and DIV 21 when compared to the Wt (**, p<0.001; ***, p<0.0001). In each case, 17 neurons were scored and compared. The scale bar is 2 µm (TIFF 2508 kb)
401_2012_1006_MOESM3_ESM.tif (803 kb)
Figure S2. The effect of TDP-43 over-expression on the expression levels of Rac1, GTP-Rac1 and GluR1. (a) Expression levels of TDP-43, Rac1, GTP-Rac1 and GluR1 in the cultured hippocampal neuron from TDP-43 Tg mice in comparison to the Wt mice. The total proteins and RNAs from DIV 7 primary hippocampal neuron cultures from 16 day TDP-43 Tg or Wt mouse embryos were subjected to Western blotting (I) and quantitative RT-PCR (II) analysis. The statistical analysis of the levels of the Rac1, GTP-Rac1, and TDP-43 proteins are presented in the histogram. *, p < 0.05**, p < 0.001 and ***, p < 0.0001. Note the decrease of the amounts of the Rac1, GTP-Rac1 and GluR1 proteins in the TDP-43 over-expressing samples (Tg) in comparison to the Wt control. On the other hand, the level of the Rac1 mRNA in the TDP-43 Tg RNA sample is similar to that in the Wt RNA sample. (b) Representative high magnification confocal microscopic pictures showing the distribution patterns of AMPARs in cultured hippocampal neurons from TDP-43 Tg mice (Tg panels) or Wt mice (Wt panels) that were transfected with pGFP-actin at DIV 12 and immunostained at DIV 14 with [anti-Rac1(red) + anti- N-GluR1 (blue), upper 3 rows of panels] or anti - GTP-Rac1 (red, lowest row of panels). The scale bar is 1 µm long. Note the decreases of (I) the levels of Rac1 and N-GluR1, (II) the co-localization of Rac1 clusters with clusters of N-GluR1, as well as (III) the number of GTP-Rac1 clusters colocalized with protrusions. The two bar diagrams show of the percentage of protrusions with colocalized clusters of AMPAR (N-GluR1) and Rac1 (left) and the mean number GTP-Rac1 clusters with protrusions /10µm of dendrites (right), respectively. On average, 65 dendrites were analyzed in each of 3 sets of experiments, with approximately a total of 55-60 neurons studied. ***, ** and * represent significant changes with p<0.0001, p<0.001 and p<0.05 respectively (TIFF 802 kb)
401_2012_1006_MOESM4_ESM.tif (1.3 mb)
Figure S3. Golgi staining of the hippocampal neurons from adult mice. Brain sections from 6 month-old Tg and Wt mice were analysed by Golgi staining as described in the Materials and Methods. (a) Upper panels, photomicrographs of representative segments of Golgi stain-impregnated dendritic branches of the hippocampus. The boxed areas of the upper 2 panels are shown in higher magnification in the lower 2 panels. The red arrowheads point to the spines. Scale bar, 10μm. (b) Statistical analysis of the density of the dendritic spines of hippocampal neurons of the Tg mouse brain in comparison to the Wt mice. Wt, n=6; Tg, n=6. t-test, *** p < 0.0001 (TIFF 1309 kb)
401_2012_1006_MOESM5_ESM.tif (2.1 mb)
Figure S4. Rescue of TDP-43 sh1 RNA-induced changes of the dendritic spines of cultured hippocampal neurons. (a) Confocal microscopic pictures of cultured hippocampal neurons at DIV 14. (I) The hippocampal neurons were co-transfected at DIV 12 with: p-shLuc + pEF-Flag + pGFP actin, 1st column; p-shLuc + pFlag-TDP-43(mt) + pGFP actin, 2nd column; p-sh1(TDP-43) + pEF-Flag + pGFP actin, 3rd column; p-sh1(TDP-43) + pFlag-TDP-43 (mt) + pGFP-actin, 4th column. Two days later (DIV 14), the cells were stained with anti-TDP-43 (visualized with Alexa Fluor 546) and anti-Flag (visualized with Alexa Fluor 647) antibodies. Note the lower amount of TDP-43 in cells harboring the p-sh1(TDP-43) and pEF-Flag plasmids (3rd column from left) than those harboring the p-shLuc and pEF-Flag plasmids (1st column from left), indicating knockdown of TDP-43 by the sh1 RNA . This loweing of TDP-43 by the sh1 RNA was rescued by the presence of the sh1 RNA-resistant form of TDP-43, i.e., Flag-TDP-43(mt) (compare the 3rd and 4th columns). The scale bar is 20 µm. (II) Representative higher-magnification pictures showing the different structures of the dendritic protrusions. Blue arrowheads point to the filopodium-like protrusion. The red and yellow arrows point to the spines, of which the red arrows represent the mushroom- like spines. The scale bar is 2 µm. (b) Quantification of the rescuing effects of Flag-TDP-43(mt) on the sh1 RNA-induced changes of the density and the morphology of the dendritic spines. (I) Bar diagram showing the mean numbers of the spines per 10 µm of the dendrites in different samples. (II) Bar diagram showing the percentages of mushroom-like spines among the total protrusions of different samples. ***, ** and * represent significant changes with p<0.0001, p<0.001 and p<0.05 respectively (TIFF 2185 kb)
401_2012_1006_MOESM6_ESM.tif (3.6 mb)
Figure S5. Effect of TDP-43 knockdown on the morphogenesis of cultured hippocampal neurons. Cultured hippocampal neurons were co-transfected with pGFP-actin and p-sh1 (TDP-43) or p-sh2 (TDP-43) or psh-Luc at DIV 5, and analyzed at DIV 7 by immunofluorescence staining with anti-TDP-43 and anti-GFP. The bar diagrams show the comparisons of the total neurite length per neuron (a), the branch number per neuron (b), and the major shaft number per neuron (c) between the control cells and neurons with TDP-43 knockdown. 35 neurons were scored in each set of the samples (TIFF 3673 kb)
401_2012_1006_MOESM7_ESM.tif (574 kb)
Figure S6. Effect of the Rac1 inhibitor RI on the TDP-43 knockdown-induced increase of Rac1, GTP- Rac1, GluR1 and clustering of Rac1 and N-GluR1 at the dendrite surface. (a) Western blotting analysis of the expression levels of TDP-43, Rac1, GTP-Rac1 and GluR1 in the cultured hippocampal neurons with TDP-43 depletion and/or treatment with RI. DIV 10 primary hippocampal neuron cultures were transfected with TDP-43 siRNA-1 oligo (si1) or the control scRNA oligo (sc) for 48 hrs, and then treated with 50 µM Rac1 inhibitor (denoted as sc+RI and si1+RI, respectively). The total proteins were then isolated and subjected to Western blot analysis with anti-TDP-43, anti-Rac1, anti-GTP-Rac1 and anti-GluR1 antibodies. Note that Rac1 inhibitor treatment decreased the GTP-Rac1 and GluR1 levels without changing the Rac1 and TDP-43 expression (compare the left 2 lanes and the right 2 lanes, respectively). (b) Left, representative high magnification confocal microscopic pictures showing the distribution patterns of N-GluR1/AMPAR and Rac1 in Rac1 inhibitor-treated hippocampal neurons in culture, with or without knockdown of TDP-43.The cultured hippocampal neurons were co-transfected with pGFP-actin, p-shLuc (con) or with pGFP-actin, p-sh1(TDP-43) (sh1) at DIV 12. The cultures were then treated with 50µM of Rac1 inhibitor at DIV 14 (denoted as con+RI and sh1+RI), co-immunostained with anti-Rac1(red) and anti-N-GluR1 (blue). The scale bar is 2 µm long. Right, quantification of the effects of Rac1 inhibitor treatment on the appearance of the N-GluR1/AMPAR clusters and their co-localization with Rac1 at the dendritic protrusions of cultured hippocampal neurons with or without TDP-43 knockdown. The bar diagram shows the % of protrusions with colocalized clusters of N-GluR1 and Rac1. For each set, 32-35 neurons were analyzed. *** and ** represent significant changes with p<0.0001 and p<0.001, respectively (TIFF 574 kb)
401_2012_1006_MOESM8_ESM.tif (1.7 mb)
Figure S7. Rescue of TDP-43 sh1 RNA-induced changes of the immunostaining patterns of Rac1, GTP-Rac1, GluR1 and synaptophysin of cultured hippocampal neurons. Representative confocal microscopic pictures (left) of cultured hippocampal neurons co-transfected at DIV 12 with p-sh1(TDP-43) + pEF-Flag + pGFP actin (1st row) and p-sh1(TDP-43) + pFlag-TDP-43 (mt) + pGFP-actin (2nd row) and analyzed by immunostaining at DIV 14. The data of the statistical analysis are shown in the histograms on the right. (a) The transfected hippocampal neurons were co-stained with anti-TDP-43, anti-Flag and anti Rac1. (b) The transfected hippocampal neurons were immunostained with anti-GTP-Rac1, anti-GluR1, or anti–synaptophysin. Note the rescues (decrease) of the sh1(TDP-43)-induced increases of Rac1 [compare the 2 panels of the right column of (a)], GTP-Rac1 [compare the 2 panels of the left column of (b)], GluR1 [compare the 2 panels of the middle column of (b)], and synaptophysin [compare the 2 panels of the right column of (b)], by the exogenous expression of Flag-TDP-43 (mt). The scale bars are 20 µm. ** and * represent significant changes with p<0.001 and p<0.05, respectively. For each set of the immunostaining experiments, a total of 12-20 neurons in two different culture samples were analyzed (TIFF 1782 kb)
401_2012_1006_MOESM9_ESM.tif (1.9 mb)
Figure S8. Altered mEPSCs in the primary hippocampal culture transfected with p-sh1TDP-43. Whole-cell voltage clamp recordings of cultured hippocampal neurons (7-8 DIV) transfected with p-shLuc (Control), p-sh1 (TDP-43), or p-sh2 (TDP-43) were performed. Representative traces of the mEPSCs recorded from the neurons transfected with p-shLuc and p-sh1 (TDP-43) are shown in (a). Comparisons of the amplitudes (I), frequencies (II), rise τ (III) and decay τ (IV) of the mEPSCs are shown as the histograms in (b). ** and *** represent significant changes with p <0.001 and p < 0.0001, respectively. The scale bars are 20 pA and 1s, respectively. The results represent the mean ± SEM of three independent experiments (n=12 neurons/experiment) (TIFF 1930 kb)
401_2012_1006_MOESM10_ESM.tif (932 kb)
Figure S9. Effect of TDP-43 depletion on Neuro 2A cells. Neuro 2A cells grown on coverslip coated with poly L Lysine were transfected with the control siRNA oligo (sc) or the TDP-43 siRNA oligo 1 (si 1) for 48 hr. The proteins were then isolated and analyzed by Western blotting analysis with use of anti-TDP-43, anti-Rac1 anti-GTP-Rac1 and anti-actin antibodies. The transfected cells were also treated for 2 hr with retinoic acid (RA) to induce differentiation, and the neurite outgrowth of the cells were examined under the microscope. Unlike the cultured hippocampal neurons, TDP-43 knockdown by the sil oligo did not increase the level of Rac1 and GTP-Rac 1 in Neuro 2A cells, as seen in the Western blot in (a). Also, TDP-43 knockdown by sil oligo inhibited the neurite outgrowth (b), similar to the observation by Iguchi et al. (2009) (TIFF 931 kb)
401_2012_1006_MOESM11_ESM.tif (1.6 mb)
Figure S10. Developmental changes of the expression levels of the endogenous TDP-43 and Rac1 in the primary hippocampal neuron cultures. (a) Left, Western blotting patterns of TDP-43, Rac1 and actin of the Wt hippocampal neurons in culture at DIV 7d, 14d, and 21d. Right, the same experiment was carried out with the TDP-43 Tg hippocampal neurons is culture. (b) Statistical analysis of the relative levels of Rac1 (left diagram) and TDP-43 (right diagram) at DIV 7, 14, and 21, as deduced from the Western blotting analysis. The expression levels were normalized to that of the actin and the relative intensity of the Wt sample at DIV 7 was taken as 1. Note the increasingly higher levels of the endogenous Rac1 protein at DIV 14 and DIV 21 in comparison to that at DIV 7, and the similarly low amounts of Rac1 in the Tg and Wt samples at DIV 7. Also, the rate of increase of Rac1 protein level in the Tg samples is much smaller that of the Wt. In contrast, the levels of the TDP-43 of both the Wt and Tg hippocampal neurons decreased during the development in culture. Data represent the mean ± SEM (error bars; n = 3). **, p<0.001 and ***, p<0.0001 (TIFF 1636 kb)

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Pritha Majumder
    • 1
  • Yi-Ting Chen
    • 2
  • Jayarama Krishnan Bose
    • 1
  • Cheng-Chun Wu
    • 3
  • Wei-Cheng Cheng
    • 1
  • Sin-Jhong Cheng
    • 4
  • Yen-Hsin Fang
    • 1
  • Ying-Ling Chen
    • 1
  • Kuen-Jer Tsai
    • 3
    • 5
  • Cheng-Chang Lien
    • 6
  • Che-Kun James Shen
    • 1
    • 2
  1. 1.Institute of Molecular BiologyAcademia SinicaTaipeiTaiwan
  2. 2.Institute of Genome SciencesNational Yang-Ming UniversityTaipeiTaiwan
  3. 3.Institute of Basic Medical ScienceNational Cheng Kung UniversityTainanTaiwan
  4. 4.Neural Circuit ElectrophysiologyNPAS, Academia SinicaTaipeiTaiwan
  5. 5.Institute of Clinical MedicineNational Cheng Kung UniversityTainanTaiwan
  6. 6.Institute of NeuroscienceNational Yang-Ming UniversityTaipeiTaiwan

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