肌萎縮性脊髓側索硬化症相關之TDP-43突變蛋白質的結構與生化特性分析

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研究生：	江建豪 Chiang, Chien Hao
論文名稱：	肌萎縮性脊髓側索硬化症相關之TDP-43突變蛋白質的結構與生化特性分析 Structural and biochemical properties of the ALS-linked mutations in TDP-43
指導教授：	袁小琀 Yuan, Hanna S. 呂平江 Lyu, Ping Chiang
口試委員:	蕭育源蕭傳鐙孫玉珠蘇士哲
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生物資訊與結構生物研究所 Institute of Bioinformatics and Structural Biology
論文出版年：	2016
畢業學年度：	104
語文別：	英文
中文關鍵詞：	肌萎縮性脊髓側索硬化症、TDP-43 、突變、結構、漸凍人
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TDP-43為一能與核醣核酸結合的蛋白質，在細胞中具有多重的功能，包含基因轉錄的抑制、轉譯的調節、調控訊息RNA的剪接與運輸。另一方面TDP-43會被蛋白酶切成較小的25 kD 和35 kD片段，進而形成聚合體並在神經細胞中沉積，此現象與多種神經退化性疾病有關，包含肌萎縮性脊髓側索硬化症(漸凍人)。近年來陸續在漸凍人病患中發現帶有近50個TDP-43的胺基酸點突變，然而我們並不清楚這些TDP-43突變，是否會造成蛋白質生化或結構特性上的改變，而與疾病有相關連。這份論文報告中我們試圖純化數個與漸凍人相關的TDP-43點突變蛋白質，來瞭解此蛋白質具有哪些特性上的改變。我們純化了八個TDP-43點突變蛋白質，藉由圓二色光譜儀與螢光儀的實驗，我們發現兩個突變蛋白質D169G與M311V，與野生種TDP-43相比具有較高的熱耐受性。為了探討可能的原因，我們解析了包含D169G突變的RRM1 (RRM1-D169G)區塊與DNA結晶的複合物的晶體結構。我們發現相較於野生種RRM1結構，RRM1-D169G的晶體結構中，G169與T115之間的氫鍵消失，而造成一個轉折區域（Turn6）輕微的移動。配合動力學模擬試驗，進一步發現這個轉折區域的移動，造成RRM1區塊內部形成更緊密的交互作用，因此增加了蛋白質的整體穩定度。我們還發現TDP-43含有D169G突變的蛋白質，與野生種TDP-43相比，較易於被caspase 3蛋白酶分解成約35 kD的片段。在神經細胞中表現的TDP-43 D169G的全長突變蛋白質，也較易被降解成35 kD的片段。根據這些結果，我們建議D169G的突變會使得TDP-43較容易被蛋白酶所降解，並產生了較為穩定的35 kD片段，此片段的增加與蛋白質的堆積與疾病成因密切相關。我們的研究說明了TDP-43蛋白質的穩定度是與疾病相關的一個重要因數，調控TDP-43的穩定度或是蛋白酶降解的速率，可能是一個有效的方式，來防止或治療TDP-43相關的神經退化性疾病。

TDP-43 is an RNA/DNA-binding protein, playing multiple roles in transcription repression, translation regulation, mRNA splicing and mRNA transport. However, TDP-43 is cleaved into 25-kD and 35-kD C-terminal fragments (TDP-25 and TDP-35) and aggregated in neuronal cells linking to various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). About 50 mutations in TDP-43 have been identified in ALS patients, but it is unclear why these mutations are linked to protein aggregation and ALS. Here we purified eight ALS-linked TDP-43 mutants and found that two of the mutants, D169G and M311V, had increased thermal stability as measured by circular dichroism and differential scanning fluorimetry. To decipher the structural basis for the increased thermal stability, we determined the crystal structure of the TDP-43 RRM1 domain with D169G mutation (RRM1-D169G) in complex with a single-stranded DNA. We found that a β-turn (Turn6) in RRM1 is slightly shifted due to the loss of a hydrogen bond between G169 and T115 in RRM1-D169G. The molecular dynamic simulation further showed that the D169G increases the hydrophobic interactions in the core of the RRM1 domain, thus enhancing protein stability. Moreover, comparing to the wild type, TDP-43 with D169G mutation was cleaved more efficiently than the wild-type by caspase 3 to yield TDP-35 that may initiate protein accumulation. Consistently, expression of TDP-43 with D169G mutation in Neuro2a cells produced higher level of TDP-35 than that of wild-type protein. Taken together these results provide the structural basis for the increased stability of the TDP-43 D169G mutant, and demonstrate that D169G is more susceptible to proteolytic cleavage by caspase 3 into the stable pathogenic C-terminal 35-kD fragments that can promote protein accumulation and aggregation. Our results suggest that protein stability is an important factor for regulating TDP-43 accumulation and aggregation. Modulation of TDP-43 protein stability and caspase digesting rate could offer an avenue for prevention and treatment of neurodegenerative diseases related to TDP-43 proteinopathy.

CONTENTS
CONTENTS    i
CONTENT OF TABLES    iv
CONTENT OF FIGURES    v
1.    INTRODUCTION    1
1.1    TDP-43 has multiple cellular functions    1
1.1.1    TDP-43 functions as a transcription repressor    1
1.1.2    TDP-43 is a splicing factor    2
1.1.3    TDP-43 regulates the stability of mRNA    3
1.1.4    TDP-43 is a component of the Drosha and Dicer complexes for microRNA biogenesis    4
1.1.5    TDP-43 is involved in mRNA transportation    5
1.2    The domain structure of TDP-43    6
1.2.1    N-terminal domain (NTD)    6
1.2.2    RNA recognition motifs (RRM1and RRM2)    6
1.2.3    C-terminal glycine-rich domain    7
1.2.4    The overall structure of TDP-43    8
1.3    The pathological role of TDP-43    8
1.3.1 TDP-43 is involved in neurodegeneration diseases    8
1.3.2 Frontotemporal Lobar Degeneration (FTLD)    9
1.3.3 Amyotrophic Lateral Sclerosis (ALS)    10
1.3.4     The roles of TDP-25 and TDP-35    11
1.4    Aims of this research    12
2.    MATERIALS AND METHODS    14
2.1    Human TDP-43 constructs and site-directed mutagenesis    14
2.2    Expression and purification of recombinant TDP-43    14
2.3    SDS-PAGE and Tricine-SDS-PAGE    15
2.4    Determination of protein concentration    16
2.5    Dynamic light scattering (DLS)    17
2.6    Circular dichroism    17
2.7    Differential scanning fluorimetry    18
2.8    Caspases digestion assays    18
2.9    Crystallization and X-ray data collection    19
2.10    Crystal structure determination and refinement    19
2.11    Molecular dynamics simulation    20
2.12    Cell cultures, Stable cell line generation and protein degradation assays    20
2.13    Statistical analysis    21
2.14    Small angle X-ray scattering (SAXS) and data analysis    22
3.    RESULTS    23
3.1    Overexpression and purification of TDP-43    23
3.2    D169G and M311V mutants exhibit increased thermal stability    23
3.3    D169G is more efficiently cleaved by caspase 3 to TDP-35    25
3.4    Overall crystal structure of RRM1-D169G in complex with DNA    26
3.5    Local structural variations of RRM1-D169G as compared to the wild-type RRM1    28
3.6    The D169G mutant has increased hydrophobic core interactions revealed by MD simulations    29
3.7    Increased levels of TDP-35 for D169G mutant by in vivo assays    31
3.8    The role of Cys residues in NTD in protein oligomerization and stability    32
3.9    The oligomer states of NTD determined by SAXS    33
4.    DISCUSSION    35
4.1    D169G mutation in TDP-43 produces a more stable protein than wild type    35
4.2    The role of NTD in TDP-43    37
REFERENCES    39
APPENDIX    86











CONTENT OF TABLES
Table 1. ALS-linked mutations in human TDP-43.    53
Table2. The primers used for TDP-43 constructs and site-directed mutagenesis.    54
Table 3. Thermal melting points (Tm) of TDP-43 measured by circular dichroism (CD) and differential scanning fluorimetry (DSF).    55
Table 4. Crystallographic statistics of RRM1/DNA and RRM1-D169G/DNA complex.    56
Table 5. The molecular surface area of RRM1 and RRM1-D169G.    57
Table 6. Theoretical and experimental molecular weights and scattering parameters for NTD of human TDP-43.    58








CONTENT OF FIGURES
Figure 1. The sequence alignment of human TDP-43 and mouse TDP-43.     59
Figure 2. The proposed physiological roles of TDP-43.     60
Figure 3. The reported three-dimensional structures of TDP-43.    61
Figure 4. The ab initio SAXS envelope of TDP-43 (N-RRM12).    62
Figure 5. Domain structures and ALS-linked mutations of TDP-43.    63
Figure 6. Various TDP-43 deletion contructs were made in this thesis.    64
Figure 7. Purification of TDP-43 proteins (RRM1-D169G as the example).    65
Figure 8. Gel-filtration and DLS profiles of RRM1-WT and RRM1-D169G.    66
Figure 9. SDS–PAGE analysis of the purified TDP-43 proteins.    67
Figure 10. The CD spectra and Tm estimation for TDP-43 proteins.    68
Figure 11. The melting point analysis of TDP-43 by differential scanning fluorimetry.    69
Figure 12. Caspases digestion assays of N-RRM12 and mutants.    70
Figure 13. Crystals and the crystallization conditions of RRM1-WT and RRM1-D169G.    71
Figure 14. The overall crystal structures of RRM1-WT and RRM1-D169G.    72
Figure 15. The close view of RRM1-D169G/DNA complex.     73
Figure 16. The interactions between RRM1 and DNA.     74
Figure 17. The superimposition of RRM1/DNA determined previously with RRM1/DNA and RRM1-D169G/DNA determined in this study.    75
Figure 18. A close look at Turn6 in the RRM1 and D169G mutant.    76
Figure 19. The superimposition of the crystal structure of RRM1-D169G with RRM1 structures determined by NMR.    77
Figure 20. The molecular dynamics simulations between RRM1 and D169G.    78
Figure 21. Increased TDP-35 fragments of D169G mutant in vivo.    79
Figure 22. The N-terminal domain (NTD) of TDP-43 forms primarily a homodimer.    80
Figure 23. The TDP-43 NTD with the C39A muation forms a stable dimer.    81
Figure 24. MASS spectra of NTD-C39A and NTD-C50A.    82
Figure 25. SAXS profiles and models of NTD-WT and NTD-C39A.    83
Figure 26. The ab initio SAXS envelope of NTD-C39A.    84
Figure 27. A model for TDP-43 cleavage, accumulation and inclusion formation.    85

                                

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