臺灣博碩士論文加值系統

早衰症是一種基因表現失調造成之罕見遺傳疾病。到目前為止，已發現許多不同類型的早衰症，而Cutis Laxa是其中之一，其常見症狀包含掉髮、視力下降、多餘和鬆垮的肌膚。在2009年發現Cutis Laxa患者pycr1基因常有突變，但其致病機制仍不清楚 。本論文乃研究pycr1突變斑馬魚老化相關表徵已確立其可為Cutis Laxa實驗動物模型，並嘗試探討pycr1突變導致Cutis Laxa 的致病機轉。實驗中發現pycr1基因高量表現於成魚及幼魚腸道，且其雄性pycr1突變斑馬成魚體重較對照組低。測試幼魚，發現pycr1突變魚攝食量低於對照組。另一方面pycr1突變幼魚細胞凋亡和衰老現象亦增加。因過去已知pycr1在粒腺體大量表現，我進一步發現在早期發育階段，pycr1突變幼魚粒Cutis Laxa體DNA拷貝數顯著較低，卻在發育晚期恢復到正常水平，其可能藉由pycr2的補償作用造成，因我觀察到在這之前pycr2基因表現增高。總體而言，藉由剔除pycr1，斑馬魚可成為很好的早衰症模式動物以探討其致病機轉。

Progeria also known as premature aging is an extremely rare genetic disorder. Up to now, there are several types of progeria described. Cutis Laxa is one of progeria diseases and patients have common aging symptoms such as hair loss, deterioration of eyesight, redundant and inelastic skin. In 2009, mutations in pycr1 gene had been found in Cutis Laxa patients. The paper is, however, one of few mechanistic studies about pycr1-dependent progeria due to the rareness and lack of animal models. Therefore, I aimed to characterize the aging-related phenotypes of pycr1-/- zebrafish and use them to understand how pycr1 causes Cutis Laxa. I first showed spatial and temporal expression of pycr1 gene in zebrafish. In particular, the pycr1 gene is highly expressed in guts of both larvae and adult fish. Pycr1-/-males exhibited lower body weight. Therefore, I first measured food intake and found that pycr1-/- larvae indeed ate less than that of controls. Apoptosis and cellular senescence were also increased in pycr1-/- zebrafish. Pycr1 is a mitochondria-enriched enzyme, so I examined mitochondrial DNA copy number and found it is significantly decreased in early pycr1-/- larvae, but is restored by 5 day post fertilization which might be due to compensatory effect of Pycr2. Overall, this study shows molecular and physiological defects in the absence of pycr1 that could possibly contribute to our understanding the mechanisms of premature aging.

Table of Content

CHINESE ABSTRACT 1
ABSTRACT 2
INTRODUCTION 3
Telomeres in progeria 3
Cellular senescence and cell cycle regulation in progeria 4
Mitochondrial dysfunction in progeria 5
Current knowledge about cutis laxa syndrome and pycr1 6
METHODS 9
Zebrafish maintenance 9
Microinjection 9
In silica analysis of pycr1 gene 9
Polymerase Chain Reaction (PCR) 10
Preparation of fluorescence-labelled paramecia and monitoring of larval food intake 10
RNA extraction and cDNA preparation 11
Whole mount in situ hybridization 11
Senescence-Associated β galactosidase assay 12
QPCR 12
Relative mitochondrial DNA (mtDNA) copy number analysis 13
TUNEL assay 14
Statistics 14
RESULTS 15
In silica analysis of Pycr1 gene 15
Spatial and Temporal expression of pycr1 in zebrafish 15
Pycr1 mutant males exhibited lower body weight 16
Loss of PYCR1 affects food intake 17
Pycr1-/- zebrafish showed higher SA-β gal activity during development 18
Loss of PYCR1 induced apoptosis determined by TUNEL assay 18
Mitochondrial copy number was affected in early stages 19
Pycr2 compensated the severe mitochondrial phenotype possibly by increasing polg expression 20
Pycr1 might involve in tgf-β signaling pathway 20
DISCUSSION 22
REFERENCES 26
Figure 1. Sequence, domain and function analyses of pycr1 36
Figure 2. Spatial and Temporal expression of pycr1 in zebrafish 38
Figure 3. Survival rate of pycr1-/- fish 39
Figure 4. pycr1-/- male exhibited lower body weight 41
Figure 5. Zebrafish food intake assay optimization 43
Figure 6. Optimization of feeding duration 45
Figure 7. Loss of Pcyr1 reduced food intake 46
Figure 8. Pycr1-/-zebrafish showed higher SA-β gal activity during development. 47
Figure 9. Loss of PYCR1 induced apoptosis determined by TUNEL assay 48
Figure 10. Mitochondrial DNA copy number is effected in early stages 49
Figure 11. pycr2 compensates the severe mitochondrial phenotype possibly by increasing polg expression. 51
Figure 12. Pycr1 may involve in TGFβ signaling pathway 53
Figure 13. Toxicity of zebrafish pycr1 mRNA 54
Figure 14. Transient overexpression of pycr1 had no effect on gdf11 and alk5 56
Supplementary Figures 57
Supplementary Figure 1. Generation of pycr1-/- fish by TALEN approach 57

Akhmedov, A. T. and J. Marin-Garcia (2015). "Mitochondrial DNA maintenance: an appraisal." Mol Cell Biochem 409(1-2): 283-305.
Arancio, W., G. Pizzolanti, S. I. Genovese, M. Pitrone and C. Giordano (2014). "Epigenetic involvement in Hutchinson-Gilford progeria syndrome: a mini-review." Gerontology 60(3): 197-203.
Bailey, L. J., T. J. Cluett, A. Reyes, T. A. Prolla, J. Poulton, C. Leeuwenburgh and I. J. Holt (2009). "Mice expressing an error-prone DNA polymerase in mitochondria display elevated replication pausing and chromosomal breakage at fragile sites of mitochondrial DNA." Nucleic Acids Res 37(7): 2327-2335.
Berk, D. R., D. D. Bentley, S. J. Bayliss, A. Lind and Z. Urban (2012). "Cutis laxa: a review." J Am Acad Dermatol 66(5): 842 e841-817.
Bestman, J. E., K. D. Stackley, J. J. Rahn, T. J. Williamson and S. S. L. Chan (2015). "The cellular and molecular progression of mitochondrial dysfunction induced by 2,4-dinitrophenol in developing zebrafish embryos." Differentiation; research in biological diversity 89(0): 51-69.
Breitbart, E., H. Mensing and W. Meigel (1981). "[Surgical treatment of skin changes in cutis laxa (author''s transl)]." Z Hautkr 56(2): 90-97.
Bridger, J. M. and I. R. Kill (2004). "Aging of Hutchinson-Gilford progeria syndrome fibroblasts is characterised by hyperproliferation and increased apoptosis." Exp Gerontol 39(5): 717-724.
Cao, K., C. D. Blair, D. A. Faddah, J. E. Kieckhaefer, M. Olive, M. R. Erdos, E. G. Nabel and F. S. Collins (2011). "Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts." J Clin Invest 121(7): 2833-2844.
Carrero, D., C. Soria-Valles and C. López-Otín (2016). "Hallmarks of progeroid syndromes: lessons from mice and reprogrammed cells." Disease Models & Mechanisms 9(7): 719-735.
Cerella, C., C. Grandjenette, M. Dicato and M. Diederich (2016). "Roles of Apoptosis and Cellular Senescence in Cancer and Aging." Curr Drug Targets 17(4): 405-415.
Chatre, L., D. S. Biard, A. Sarasin and M. Ricchetti (2015). "Reversal of mitochondrial defects with CSB-dependent serine protease inhibitors in patient cells of the progeroid Cockayne syndrome." Proc Natl Acad Sci U S A 112(22): E2910-2919.
Childs, B. G., M. Durik, D. J. Baker and J. M. van Deursen (2015). "Cellular senescence in aging and age-related disease: from mechanisms to therapy." Nat Med 21(12): 1424-1435.
Clay Montier, L. L., J. J. Deng and Y. Bai (2009). "Number matters: control of mammalian mitochondrial DNA copy number." J Genet Genomics 36(3): 125-131.
Copeland, W. C. (2010). "The mitochondrial DNA polymerase in health and disease." Subcell Biochem 50: 211-222.
Crabbe, L., A. Jauch, C. M. Naeger, H. Holtgreve-Grez and J. Karlseder (2007). "Telomere dysfunction as a cause of genomic instability in Werner syndrome." Proceedings of the National Academy of Sciences of the United States of America 104(7): 2205-2210.
Cree, L. M., S. K. Patel, A. Pyle, S. Lynn, D. M. Turnbull, P. F. Chinnery and M. Walker (2008). "Age-related decline in mitochondrial DNA copy number in isolated human pancreatic islets." Diabetologia 51(8): 1440-1443.
DeBalsi, K. L., K. E. Hoff and W. C. Copeland (2017). "Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases." Ageing Res Rev 33: 89-104.
Decker, M. L., E. Chavez, I. Vulto and P. M. Lansdorp (2009). "Telomere length in Hutchinson-Gilford progeria syndrome." Mech Ageing Dev 130(6): 377-383.
Dimopoulou, A., B. Fischer, T. Gardeitchik, P. Schröter, H. Kayserili, C. Schlack, Y. Li, J. M. Brum, I. Barisic, M. Castori, C. Spaich, E. Fletcher, Z. Mahayri, M. Bhat, K. M. Girisha, K. Lachlan, D. Johnson, S. Phadke, N. Gupta, M. Simandlova, M. Kabra, A. David, L. Nijtmans, D. Chitayat, B. Tuysuz, F. Brancati, S. Mundlos, L. Van Maldergem, E. Morava, B. Wollnik and U. Kornak (2013). "Genotype–phenotype spectrum of PYCR1-related autosomal recessive cutis laxa." Molecular Genetics and Metabolism 110(3): 352-361.
Dimri, G. P., X. Lee, G. Basile, M. Acosta, G. Scott, C. Roskelley, E. E. Medrano, M. Linskens, I. Rubelj, O. Pereira-Smith and et al. (1995). "A biomarker that identifies senescent human cells in culture and in aging skin in vivo." Proc Natl Acad Sci U S A 92(20): 9363-9367.
Ding, J., M. L. Kuo, L. Su, L. Xue, F. Luh, H. Zhang, J. Wang, T. G. Lin, K. Zhang, P. Chu, S. Zheng, X. Liu and Y. Yen (2017). "Human Mitochondrial Pyrroline-5-Carboxylate Reductase 1 Promotes Invasiveness and Impacts Survival in Breast Cancers." Carcinogenesis.
Ding, S. L. and C. Y. Shen (2008). "Model of human aging: recent findings on Werner''s and Hutchinson-Gilford progeria syndromes." Clin Interv Aging 3(3): 431-444.
Dominguez-Gerpe, L. and D. Araujo-Vilar (2008). "Prematurely aged children: molecular alterations leading to Hutchinson-Gilford progeria and Werner syndromes." Curr Aging Sci 1(3): 202-212.
Edgar, D. and A. Trifunovic (2009). "The mtDNA mutator mouse: Dissecting mitochondrial involvement in aging." Aging (Albany NY) 1(12): 1028-1032.
Finley, J. (2014). "Alteration of splice site selection in the LMNA gene and inhibition of progerin production via AMPK activation." Med Hypotheses 83(5): 580-587.
Fischer, B., A. Dimopoulou, J. Egerer, T. Gardeitchik, A. Kidd, D. Jost, H. Kayserili, Y. Alanay, I. Tantcheva-Poor, E. Mangold, C. Daumer-Haas, S. Phadke, R. I. Peirano, J. Heusel, C. Desphande, N. Gupta, A. Nanda, E. Felix, E. Berry-Kravis, M. Kabra, R. A. Wevers, L. van Maldergem, S. Mundlos, E. Morava and U. Kornak (2012). "Further characterization of ATP6V0A2-related autosomal recessive cutis laxa." Hum Genet 131(11): 1761-1773.
Galant, D., B. Gaborit, C. Desgrouas, I. Abdesselam, M. Bernard, N. Levy, F. Merono, C. Coirault, P. Roll, A. Lagarde, N. Bonello-Palot, P. Bourgeois, A. Dutour and C. Badens (2016). "A Heterozygous ZMPSTE24 Mutation Associated with Severe Metabolic Syndrome, Ectopic Fat Accumulation, and Dilated Cardiomyopathy." Cells 5(2).
Hayflick, L. and P. S. Moorhead (1961). "The serial cultivation of human diploid cell strains." Experimental Cell Research 25(3): 585-621.
He, T., T. Quan, Y. Shao, J. J. Voorhees and G. J. Fisher (2014). "Oxidative exposure impairs TGF-beta pathway via reduction of type II receptor and SMAD3 in human skin fibroblasts." Age (Dordr) 36(3): 9623.
Heatwole, V. M. (1999). "TUNEL assay for apoptotic cells." Methods Mol Biol 115: 141-148.
Indo, H. P., H. C. Yen, I. Nakanishi, K. Matsumoto, M. Tamura, Y. Nagano, H. Matsui, O. Gusev, R. Cornette, T. Okuda, Y. Minamiyama, H. Ichikawa, S. Suenaga, M. Oki, T. Sato, T. Ozawa, D. K. Clair and H. J. Majima (2015). "A mitochondrial superoxide theory for oxidative stress diseases and aging." J Clin Biochem Nutr 56(1): 1-7.
Kaczanowski, S. (2016). "Apoptosis: its origin, history, maintenance and the medical implications for cancer and aging." Phys Biol 13(3): 031001.
Kimmel, C. B., W. W. Ballard, S. R. Kimmel, B. Ullmann and T. F. Schilling (1995). "Stages of embryonic development of the zebrafish." Dev Dyn 203(3): 253-310.
Kishi, S., P. E. Bayliss, J. Uchiyama, E. Koshimizu, J. Qi, P. Nanjappa, S. Imamura, A. Islam, D. Neuberg, A. Amsterdam and T. M. Roberts (2008). "The identification of zebrafish mutants showing alterations in senescence-associated biomarkers." PLoS Genet 4(8): e1000152.
Kuo, M. L., M. B. Lee, M. Tang, W. den Besten, S. Hu, M. J. Sweredoski, S. Hess, C. M. Chou, C. A. Changou, M. Su, W. Jia, L. Su and Y. Yen (2016). "PYCR1 and PYCR2 Interact and Collaborate with RRM2B to Protect Cells from Overt Oxidative Stress." Sci Rep 6: 18846.
Levy, R., M. Benchaib, H. Cordonier, C. Souchier and J. F. Guerin (1998). "Annexin V labelling and terminal transferase-mediated DNA end labelling (TUNEL) assay in human arrested embryos." Mol Hum Reprod 4(8): 775-783.
Li, T., X. Liu, L. Jiang, J. Manfredi, S. Zha and W. Gu (2016). "Loss of p53-mediated cell-cycle arrest, senescence and apoptosis promotes genomic instability and premature aging." Oncotarget 7(11): 11838-11849.
Liu, Y., Y. Wang, A. E. Rusinol, M. S. Sinensky, J. Liu, S. M. Shell and Y. Zou (2008). "Involvement of xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A." FASEB J 22(2): 603-611.
Loayza-Puch, F., K. Rooijers, L. C. Buil, J. Zijlstra, J. F. Oude Vrielink, R. Lopes, A. P. Ugalde, P. van Breugel, I. Hofland, J. Wesseling, O. van Tellingen, A. Bex and R. Agami (2016). "Tumour-specific proline vulnerability uncovered by differential ribosome codon reading." Nature 530(7591): 490-494.
Loeb, L. A., D. C. Wallace and G. M. Martin (2005). "The mitochondrial theory of aging and its relationship to reactive oxygen species damage and somatic mtDNA mutations." Proc Natl Acad Sci U S A 102(52): 18769-18770.
Lopez-Mejia, I. C., M. de Toledo, C. Chavey, L. Lapasset, P. Cavelier, C. Lopez-Herrera, K. Chebli, P. Fort, G. Beranger, L. Fajas, E. Z. Amri, F. Casas and J. Tazi (2014). "Antagonistic functions of LMNA isoforms in energy expenditure and lifespan." EMBO Rep 15(5): 529-539.
Maierhofer, A., J. Flunkert, J. Oshima, G. M. Martin, T. Haaf and S. Horvath (2017). "Accelerated epigenetic aging in Werner syndrome." Aging (Albany NY).
Mengel-From, J., M. Thinggaard, C. Dalgard, K. O. Kyvik, K. Christensen and L. Christiansen (2014). "Mitochondrial DNA copy number in peripheral blood cells declines with age and is associated with general health among elderly." Hum Genet 133(9): 1149-1159.
Miquel, J. (1991). "An integrated theory of aging as the result of mitochondrial-DNA mutation in differentiated cells." Arch Gerontol Geriatr 12(2-3): 99-117.
Monickaraj, F., S. Aravind, K. Gokulakrishnan, C. Sathishkumar, P. Prabu, D. Prabu, V. Mohan and M. Balasubramanyam (2012). "Accelerated aging as evidenced by increased telomere shortening and mitochondrial DNA depletion in patients with type 2 diabetes." Mol Cell Biochem 365(1-2): 343-350.
O''Brien, I. E., C. P. Reutelingsperger and K. M. Holdaway (1997). "Annexin-V and TUNEL use in monitoring the progression of apoptosis in plants." Cytometry 29(1): 28-33.
Pegoraro, G. and T. Misteli (2009). "The central role of chromatin maintenance in aging." Aging (Albany NY) 1(12): 1017-1022.
Peinado, J. R., P. M. Quiros, M. R. Pulido, G. Marino, M. L. Martinez-Chantar, R. Vazquez-Martinez, J. M. Freije, C. Lopez-Otin and M. M. Malagon (2011). "Proteomic profiling of adipose tissue from Zmpste24-/- mice, a model of lipodystrophy and premature aging, reveals major changes in mitochondrial function and vimentin processing." Mol Cell Proteomics 10(11): M111 008094.
Pyle, A., H. Anugrha, M. Kurzawa-Akanbi, A. Yarnall, D. Burn and G. Hudson (2016). "Reduced mitochondrial DNA copy number is a biomarker of Parkinson''s disease." Neurobiol Aging 38: 216 e217-210.
Rahn, J. J., J. E. Bestman, K. D. Stackley and S. S. Chan (2015). "Zebrafish lacking functional DNA polymerase gamma survive to juvenile stage, despite rapid and sustained mitochondrial DNA depletion, altered energetics and growth." Nucleic Acids Res 43(21): 10338-10352.
Reversade, B., N. Escande-Beillard, A. Dimopoulou, B. Fischer, S. C. Chng, Y. Li, M. Shboul, P. Y. Tham, H. Kayserili, L. Al-Gazali, M. Shahwan, F. Brancati, H. Lee, B. D. O''Connor, M. Schmidt-von Kegler, B. Merriman, S. F. Nelson, A. Masri, F. Alkazaleh, D. Guerra, P. Ferrari, A. Nanda, A. Rajab, D. Markie, M. Gray, J. Nelson, A. Grix, A. Sommer, R. Savarirayan, A. R. Janecke, E. Steichen, D. Sillence, I. Hausser, B. Budde, G. Nurnberg, P. Nurnberg, P. Seemann, D. Kunkel, G. Zambruno, B. Dallapiccola, M. Schuelke, S. Robertson, H. Hamamy, B. Wollnik, L. Van Maldergem, S. Mundlos and U. Kornak (2009). "Mutations in PYCR1 cause cutis laxa with progeroid features." Nat Genet 41(9): 1016-1021.
Rivera-Torres, J., R. Acin-Perez, P. Cabezas-Sanchez, F. G. Osorio, C. Gonzalez-Gomez, D. Megias, C. Camara, C. Lopez-Otin, J. A. Enriquez, J. L. Luque-Garcia and V. Andres (2013). "Identification of mitochondrial dysfunction in Hutchinson-Gilford progeria syndrome through use of stable isotope labeling with amino acids in cell culture." J Proteomics 91: 466-477.
Rooney, J. P., I. T. Ryde, L. H. Sanders, E. H. Howlett, M. D. Colton, K. E. Germ, G. D. Mayer, J. T. Greenamyre and J. N. Meyer (2015). "PCR based determination of mitochondrial DNA copy number in multiple species." Methods Mol Biol 1241: 23-38.
Shimada, Y., M. Hirano, Y. Nishimura and T. Tanaka (2012). "A High-Throughput Fluorescence-Based Assay System for Appetite-Regulating Gene and Drug Screening." PLoS ONE 7(12): e52549.
Sieprath, T., T. D. Corne, M. Nooteboom, C. Grootaert, A. Rajkovic, B. Buysschaert, J. Robijns, J. L. Broers, F. C. Ramaekers, W. J. Koopman, P. H. Willems and W. H. De Vos (2015). "Sustained accumulation of prelamin A and depletion of lamin A/C both cause oxidative stress and mitochondrial dysfunction but induce different cell fates." Nucleus 6(3): 236-246.
Sinha, M., Y. C. Jang, J. Oh, D. Khong, E. Y. Wu, R. Manohar, C. Miller, S. G. Regalado, F. S. Loffredo, J. R. Pancoast, M. F. Hirshman, J. Lebowitz, J. L. Shadrach, M. Cerletti, M. J. Kim, T. Serwold, L. J. Goodyear, B. Rosner, R. T. Lee and A. J. Wagers (2014). "Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle." Science 344(6184): 649-652.
Song, Z., Y. Cao and D. C. Samuels (2011). "Replication pauses of the wild-type and mutant mitochondrial DNA polymerase gamma: a simulation study." PLoS Comput Biol 7(11): e1002287.
Szoka, L., E. Karna, K. Hlebowicz-Sarat, J. Karaszewski and J. A. Palka (2017). "Exogenous proline stimulates type I collagen and HIF-1alpha expression and the process is attenuated by glutamine in human skin fibroblasts." Mol Cell Biochem.
Thisse, C., B. Thisse, T. F. Schilling and J. H. Postlethwait (1993). "Structure of the zebrafish snail1 gene and its expression in wild-type, spadetail and no tail mutant embryos." Development 119(4): 1203-1215.
Tilstra, J. S., A. R. Robinson, J. Wang, S. Q. Gregg, C. L. Clauson, D. P. Reay, L. A. Nasto, C. M. St Croix, A. Usas, N. Vo, J. Huard, P. R. Clemens, D. B. Stolz, D. C. Guttridge, S. C. Watkins, G. A. Garinis, Y. Wang, L. J. Niedernhofer and P. D. Robbins (2012). "NF-kappaB inhibition delays DNA damage-induced senescence and aging in mice." J Clin Invest 122(7): 2601-2612.
Tivey, H. S., A. J. Brook, M. J. Rokicki, D. Kipling and T. Davis (2013). "p38 (MAPK) stress signalling in replicative senescence in fibroblasts from progeroid and genomic instability syndromes." Biogerontology 14(1): 47-62.
Trifunovic, A. and N. G. Larsson (2008). "Mitochondrial dysfunction as a cause of ageing." J Intern Med 263(2): 167-178.
Ullrich, N. J. and L. B. Gordon (2015). "Hutchinson-Gilford progeria syndrome." Handb Clin Neurol 132: 249-264.
Van Maldergem, L. and B. Loeys (1993). FBLN5-Related Cutis Laxa. GeneReviews(R). R. A. Pagon, M. P. Adam, H. H. Ardinger et al. Seattle (WA).
Varela, I., J. Cadinanos, A. M. Pendas, A. Gutierrez-Fernandez, A. R. Folgueras, L. M. Sanchez, Z. Zhou, F. J. Rodriguez, C. L. Stewart, J. A. Vega, K. Tryggvason, J. M. P. Freije and C. Lopez-Otin (2005). "Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation." Nature 437(7058): 564-568.
Vidak, S. and R. Foisner (2016). "Molecular insights into the premature aging disease progeria." Histochem Cell Biol 145(4): 401-417.
Vidak, S., N. Kubben, T. Dechat and R. Foisner (2015). "Proliferation of progeria cells is enhanced by lamina-associated polypeptide 2alpha (LAP2alpha) through expression of extracellular matrix proteins." Genes Dev 29(19): 2022-2036.
Viteri, G., Y. W. Chung and E. R. Stadtman (2010). "Effect of progerin on the accumulation of oxidized proteins in fibroblasts from Hutchinson Gilford progeria patients." Mech Ageing Dev 131(1): 2-8.
Walker, J. A. and P. Quirke (2001). "Viewing apoptosis through a ''TUNEL''." J Pathol 195(3): 275-276.
Wolthuis, D. F., E. van Asbeck, M. Mohamed, T. Gardeitchik, E. R. Lim-Melia, R. A. Wevers and E. Morava (2014). "Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature." Eur J Paediatr Neurol 18(4): 511-515.
Xiong, X. D., H. J. Jung, S. Gombar, J. Y. Park, C. L. Zhang, H. Zheng, J. Ruan, J. B. Li, M. Kaeberlein, B. K. Kennedy, Z. Zhou, X. Liu and Y. Suh (2015). "MicroRNA transcriptome analysis identifies miR-365 as a novel negative regulator of cell proliferation in Zmpste24-deficient mouse embryonic fibroblasts." Mutat Res 777: 69-78.
Xiong, Z. M., J. Y. Choi, K. Wang, H. Zhang, Z. Tariq, D. Wu, E. Ko, C. LaDana, H. Sesaki and K. Cao (2016). "Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria." Aging Cell 15(2): 279-290.
Xu, D., S. I. Jalal, G. W. Sledge and S. O. Meroueh (2016). "Small-molecule binding sites to explore protein-protein interactions in the cancer proteome." Mol Biosyst 12(10): 3067-3087.
Yasuda, T., Y. Kaji, T. Agatsuma, T. Niki, M. Arisawa, S. Shuto, H. Ariga and S. M. Iguchi-Ariga (2013). "DJ-1 cooperates with PYCR1 in cell protection against oxidative stress." Biochem Biophys Res Commun 436(2): 289-294.
Ziegler, D. V., C. D. Wiley and M. C. Velarde (2015). "Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging." Aging Cell 14(1): 1-7.