馬繼延，男，畢業於美國伊利諾伊大學芝加哥分校，現任北京腦科學與類腦研究中心資深研究員，主要研究方向為“蛋白質錯誤摺疊與神經退行性疾病。”
基本介紹
- 中文名：馬繼延
- 畢業院校：美國伊利諾伊大學芝加哥分校
人物經歷,所獲榮譽,研究概述,發表文章,
人物經歷
現任北京腦科學與類腦研寒試灶充究中心資深研究員
曾任美國范安德研究所教授；美國俄亥俄州立大學長聘(tenured)副教授；美國俄亥俄州立大學助理教授；美國芝加哥大學/霍華德休斯醫學研究所博士後研究員
所獲榮譽
· 伊利諾伊大學芝加哥分校研究生院獎學金
· 瑞士蛋白轉輸、糖基化與健康國際大會青年科學家獎
· 艾立森醫學基金會青年學者獎
· 俄亥俄州立大學醫學院優秀教學獎
亞太朊病毒協會（APSPR）理事；曾任美國NIH評審小組和研究項目計畫的常任以及即席評審專家，並任英國醫學研究委員會（MRC）和生物技術和生物科學研究委員會（BBSRC）、英國帕金森研究基金、加拿大艾伯塔省朊病毒研究所、艾伯塔Alzheimer病（老年性痴呆）研究計畫、德以科學研究基金會、以色列科學基金會、義大利衛生部、Alzheimer病基金會、美國衰老研究聯合會等國際研究機構的評審專家。
研究概述
我們研究的最終目標是闡明錯誤摺疊蛋白在神經退行性疾病中的致病機理，並研發出針對這類疾病有效的診療措施。Alzheimer病和帕金森病等神經判煮棄退行性疾病多在老年群體中發生，我們至今還沒有有效的手段來防止、治療或減緩這類疾病。日益老齡化的社會迫切需要我們對這類疾病進行深入的研究，從而開發出有效的預防、診斷和治療手段。
雖然各種遲發性神經退行性疾病的臨床表現有很大不同，但它們都具有一個共同點：在發病的中樞神經系統中都有舉精燥鞏錯誤摺疊蛋白的聚集。儘管我們知道這些蛋白聚集體的產生與疾病的發生髮展相關，但許多重要的、也是非常基本的問題依然還沒有得到回答。如這些錯誤摺疊蛋白聚集體是如何形成的？它們又是如何引起神經退行性病變的？消除這些蛋白聚集體能否減緩疾病的發展或老年性的記憶衰退？我們希望回答這些問題，從而找到治療這類疾病的方法。我們目前的研究主要集中在兩種蛋白：α-突觸核蛋白和朊蛋白。
馬繼延
α-突觸核蛋白 (α-syn)的錯誤摺疊與聚集，會導致α-突觸核蛋白病這一類神經退行性疾病。這類疾病包括帕金森病 (PD)、路易氏體失智症 (DLB) 和多系統萎縮 (MSA)等。以往的研究證明了錯誤折舉墓疊的α-syn和神經退行性變之間的相關性，然而我們還不知道為什麼α-syn會錯誤摺疊以及錯誤摺疊的α-syn如何導致神經毒性。我們將綜合套用多種現代生物學方法來研究α-syn在神經退行性疾病中的作用。利用α-syn澱粉樣纖維種籽效應的實驗模型，我們目前的研究聚焦於錯誤摺疊α-syn直接導致的分子與細胞生物學變化。此外，我們也在研究α-syn種籽效應的體外檢測方法，以期確戀邀組定α-syn聚集體的種籽活性能否發展成為可靠且方便使用的生物標誌物。
馬繼延
朊蛋白 (PrP) 是一種宿主編碼的、錨定於細胞膜上的糖蛋白。錯誤摺疊的PrP存在於一類稱為傳染性海綿狀腦病 (TSE) 或朊病毒病的神經退行性疾病中，其中包括人的克雅氏病、羊的搔癢病以及鹿和麋鹿的慢性消耗性疾病。這類神經退行性疾病的獨特之處在於它們也是傳染病。幾十年來，學界有關錯誤摺疊的PrP是否是TSE中的傳染因子（朊病毒假說）存在著激烈的爭論。我們的研究為證明這一假說提供了無可辯駁的證據。我們目前研究的一個關注點是確定PrP聚集體的哪些特徵對朊病毒的傳染性至關重要，並嘗試尋找檢測和抑制錯誤摺疊PrP的新策略。朊病毒病是齧齒動物中的神經退行性疾病，它的病理變化過程真實地反映葛辣乃了神經退行性疾病的發病過程，所以這類疾病的研究也將為揭示其他神經退行性疾病的致病機制提供啟示。另外，我們也對正常PrP的功能以及PrP在其他疾斷台乎病中的作用十分感興趣，希望揭示PrP的正常功能並通過調節PrP來輔助其他疾病的預防和治療。
發表文章
代表性文章
Prion
1. Ma Y and Ma J. (2020) Immunotherapy against prion disease. Pathogens. 9(3):216
2. Wang F, Wang X, Orrú C.D., Groveman B. R., Surewicz K., Abskharon R., Imamura M., Yokoyama T., Kim Y.S., Vander Stel K.J., Sinniah K., Priola S.A., Surewicz W.K., Caughey B., Ma J. (2017) Self-propagating, protease-resistant, recombinant prion protein conformers with or without in vivo pathogenicity. PLOS Pathog 13(7): e1006491.
3. Wang X, McGovern G, Zhang Y, Wang F, Zha L, Jeffrey M, Ma J. (2015) Intraperitoneal infection of wild-type mice with synthetically generated mammalian prion. PLOS Pathog 11(7):e1004958.
4. Ma J. (2012) The role of cofactors in prion propagation and infectivity. PLOS Pathog 8(4): e1002589.
5. Wang, F.*, Wang, X.*, Yuan, C., Ma, J. (2010) Generating a prion with bacterially expressed recombinant prion protein Science 327:1132-1135. (* equal contribution)
6. Wang, F., Yang, F., Hu, Y., Wang, X., Wang, X., Jin, C., Ma, J. (2007) Lipid interaction converts prion protein to a PrP-like proteinase K resistant conformation under physiological conditions. Biochemistry. 46(23):7045-7053.
7. Ma, J., Wollmann, R., Lindquist, S. (2002) Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol. Science 298(5599):1781-5
8. Ma, J. and Lindquist, S. (2002) Conversion of PrP to a self-perpetuating PrP-like conformation in the cytosol. Science 298(5599):1785-8
9. Ma, J. and Lindquist, S. (2001) Wild-type and mutant PrP accumulate in the cytoplasm upon proteasome inhibition Proc. Natl. Acad. Sci. USA. 98:14955-14960.
10. Ma. J. and Lindquist, S. (1999) De novo generation of a PrP-like conformation in living cells. Nat. Cell Biol. 1:358-361.
α-synuclein
1. Bargar C, Wang W, Gunzler SA, LeFevre A, Wang Z, Lerner AJ, Singh N, Tatsuoka C, Appleby B, Zhu X, Xu R, Haroutunian V, Zou W*, Ma J*, Chen SG*. (2021) Streamlined alpha-synuclein RT-QuIC assay for various biospecimens in Parkinson’s disease and dementia with Lewy Bodies. Acta Neuropathol Commun. 9(1):62. (*co-corresponding authors)
2. Wang Z, Becker K, Donadio V, Siedlak S, Yuan J, Rezaee M, Incensi A, Kuzkina A, Orrú CD, Tatsuoka C, Liguori R, Gunzler SA, Caughey B, Jimenez-Capdeville ME, Zhu X, Doppler K, Cui L, Chen SG*, Ma J*, Zou W*. (2020) Skin α-synuclein aggregation seeding activity as a novel biomarker for Parkinson’s disease. JAMA Neurol. 78(1):1-11. (*co-senior authors)
3. Roux A, Wang X, Becker K, Ma J. (2020) Modeling α-synucleinopathy in organotypic brain slice culture with preformed α-synuclein amyloid fibrils. J Parkinsons Dis. 10(4):1397-1410.
4. Marshall LL, Killinger BA, Ensink E, Li P, Li KX, Cui W, Lubben N, Weiland M, Wang X, Gordevicius J, Goetzee GA, Ma J, Jovinge S, Labrie V. (2020) Epigenomic analysis of Parkinson’s disease neurons identifies Tet2 loss as neuroprotective. Nat Neurosci. 23(10):1203-1214.
5. Wang X, Becker K, Levine N, Zhang M, Lieberman AP, Moore DJ, Ma J. (2019) Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration. Acta Neuropathol Commun. 7(1):41.
6. Chen X, Kordich JK, Williams ET, Levine N, Cole-Strauss A, Marshall L, Labrie V, Ma J, Lipton JW, Moore DJ. (2019) Parkinson’s disease-linked D620N VPS35 knockin mice manifest tau neuropathology and dopaminergic neurodegeneration. Proc Natl Acad Sci USA. 116(12):5765-5774.
7. Graham SF, Rey NL, Ugur Z, Yilmaz A, Sherman E, Maddens M, Bahado-Singh RO, Becker K, Schulz E, Meyerdirk LK, Steiner JA, Ma J, Brundin P. (2018) Metabolomic profiling of bile acids in an experimental model of prodromal Parkinson’s disease. Metabolites 8(4):71.
8. Wang B, Underwood R, Kamath A, Britain C, McFerrin MB, McLean PJ, Volpicelli-Daley LA, Whitaker RH, Placzek WJ, Becker K, Ma J, Yacoubian TA. (2018) 14-3-3 proteins reduce cell-to-cell transfer and propagation of pathogenic alpha-synuclein. J Neurosci. 38(38): 8211-8232.
9. Graham SF, Rey NL, Yilmaz A, Kumar P, Madaj Z, Maddens M, Bahado-Singh RO, Becker K, Schulz E, Meyerdirk LK, Steiner JA, Ma J, Brundin P. (2018) Biochemical profiling of the brain and blood metabolome in a mouse model of prodromal Parkinson’s disease reveal distinct metabolic profiles. J Proteome Res. 17(7): 2460-2469.
10. Becker K, Wang X, Vander Stel K, Chu Y, Kordower J, Ma J. (2018) Detecting alpha synuclein seeding activity in formaldehyde-fixed MSA patient tissue by PMCA. Mol Neurobiol. 55(11):8728-8737.
發表文章
代表性文章
Prion
1. Ma Y and Ma J. (2020) Immunotherapy against prion disease. Pathogens. 9(3):216
2. Wang F, Wang X, Orrú C.D., Groveman B. R., Surewicz K., Abskharon R., Imamura M., Yokoyama T., Kim Y.S., Vander Stel K.J., Sinniah K., Priola S.A., Surewicz W.K., Caughey B., Ma J. (2017) Self-propagating, protease-resistant, recombinant prion protein conformers with or without in vivo pathogenicity. PLOS Pathog 13(7): e1006491.
3. Wang X, McGovern G, Zhang Y, Wang F, Zha L, Jeffrey M, Ma J. (2015) Intraperitoneal infection of wild-type mice with synthetically generated mammalian prion. PLOS Pathog 11(7):e1004958.
4. Ma J. (2012) The role of cofactors in prion propagation and infectivity. PLOS Pathog 8(4): e1002589.
5. Wang, F.*, Wang, X.*, Yuan, C., Ma, J. (2010) Generating a prion with bacterially expressed recombinant prion protein Science 327:1132-1135. (* equal contribution)
6. Wang, F., Yang, F., Hu, Y., Wang, X., Wang, X., Jin, C., Ma, J. (2007) Lipid interaction converts prion protein to a PrP-like proteinase K resistant conformation under physiological conditions. Biochemistry. 46(23):7045-7053.
7. Ma, J., Wollmann, R., Lindquist, S. (2002) Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol. Science 298(5599):1781-5
8. Ma, J. and Lindquist, S. (2002) Conversion of PrP to a self-perpetuating PrP-like conformation in the cytosol. Science 298(5599):1785-8
9. Ma, J. and Lindquist, S. (2001) Wild-type and mutant PrP accumulate in the cytoplasm upon proteasome inhibition Proc. Natl. Acad. Sci. USA. 98:14955-14960.
10. Ma. J. and Lindquist, S. (1999) De novo generation of a PrP-like conformation in living cells. Nat. Cell Biol. 1:358-361.
α-synuclein
1. Bargar C, Wang W, Gunzler SA, LeFevre A, Wang Z, Lerner AJ, Singh N, Tatsuoka C, Appleby B, Zhu X, Xu R, Haroutunian V, Zou W*, Ma J*, Chen SG*. (2021) Streamlined alpha-synuclein RT-QuIC assay for various biospecimens in Parkinson’s disease and dementia with Lewy Bodies. Acta Neuropathol Commun. 9(1):62. (*co-corresponding authors)
2. Wang Z, Becker K, Donadio V, Siedlak S, Yuan J, Rezaee M, Incensi A, Kuzkina A, Orrú CD, Tatsuoka C, Liguori R, Gunzler SA, Caughey B, Jimenez-Capdeville ME, Zhu X, Doppler K, Cui L, Chen SG*, Ma J*, Zou W*. (2020) Skin α-synuclein aggregation seeding activity as a novel biomarker for Parkinson’s disease. JAMA Neurol. 78(1):1-11. (*co-senior authors)
3. Roux A, Wang X, Becker K, Ma J. (2020) Modeling α-synucleinopathy in organotypic brain slice culture with preformed α-synuclein amyloid fibrils. J Parkinsons Dis. 10(4):1397-1410.
4. Marshall LL, Killinger BA, Ensink E, Li P, Li KX, Cui W, Lubben N, Weiland M, Wang X, Gordevicius J, Goetzee GA, Ma J, Jovinge S, Labrie V. (2020) Epigenomic analysis of Parkinson’s disease neurons identifies Tet2 loss as neuroprotective. Nat Neurosci. 23(10):1203-1214.
5. Wang X, Becker K, Levine N, Zhang M, Lieberman AP, Moore DJ, Ma J. (2019) Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration. Acta Neuropathol Commun. 7(1):41.
6. Chen X, Kordich JK, Williams ET, Levine N, Cole-Strauss A, Marshall L, Labrie V, Ma J, Lipton JW, Moore DJ. (2019) Parkinson’s disease-linked D620N VPS35 knockin mice manifest tau neuropathology and dopaminergic neurodegeneration. Proc Natl Acad Sci USA. 116(12):5765-5774.
7. Graham SF, Rey NL, Ugur Z, Yilmaz A, Sherman E, Maddens M, Bahado-Singh RO, Becker K, Schulz E, Meyerdirk LK, Steiner JA, Ma J, Brundin P. (2018) Metabolomic profiling of bile acids in an experimental model of prodromal Parkinson’s disease. Metabolites 8(4):71.
8. Wang B, Underwood R, Kamath A, Britain C, McFerrin MB, McLean PJ, Volpicelli-Daley LA, Whitaker RH, Placzek WJ, Becker K, Ma J, Yacoubian TA. (2018) 14-3-3 proteins reduce cell-to-cell transfer and propagation of pathogenic alpha-synuclein. J Neurosci. 38(38): 8211-8232.
9. Graham SF, Rey NL, Yilmaz A, Kumar P, Madaj Z, Maddens M, Bahado-Singh RO, Becker K, Schulz E, Meyerdirk LK, Steiner JA, Ma J, Brundin P. (2018) Biochemical profiling of the brain and blood metabolome in a mouse model of prodromal Parkinson’s disease reveal distinct metabolic profiles. J Proteome Res. 17(7): 2460-2469.
10. Becker K, Wang X, Vander Stel K, Chu Y, Kordower J, Ma J. (2018) Detecting alpha synuclein seeding activity in formaldehyde-fixed MSA patient tissue by PMCA. Mol Neurobiol. 55(11):8728-8737.
