Positions
- Professor
-
Molecular and Human Genetics
Baylor College of Medicine
Houston, TX US
- Professor
-
Molecular & Cellular Biology
Baylor College of Medicine
Houston, Texas United States
Education
- BS from Universidad Autonoma De Madrid
- 01/1980 - Madrid, Community of Madrid Spain
- PhD from Universidad Autonoma De Madrid
- 01/1986 - Madrid, Spain
- Post-Doctoral Fellowship at Stanford University School Of Medicine
- 01/1987 - Stanford, CA United States
Professional Interests
- Comparative analysis of pathogenic mechanisms in neurodegenerative disorders
- Screens for common 'drugable' targets
Professional Statement
During the past two decades, many genes triggering neurological diseases have been identified. Some of these diseases are caused by gain of function mutations and/or impaired proteolysis of the respective proteins. Among these proteins are huntingtin (Huntington disease, HD), alpha-synuclein (Parkinson's disease, PD) and the tau and amyloid precursor proteins (in Alzheimer's disease, AD). On the other hand, diseases like Rett Syndrome are caused by loss of function mechanisms.Despite many significant advances, we still have a poor understanding of what happens between the triggering of the disease by the faulty protein and the ultimate death of the neuron. What are the molecular mechanisms and gene networks driving pathogenesis? What mechanisms are deployed by neuron and glia to compensate CNS dysfunction? Can we identify therapeutic targets common to more than one disease?
To address these questions, we integrate computational and wet-lab approaches using a combination of experimental model systems including Drosophila and mice, as well as neuronal primary cultures and iPSC-derived human neurons. Importantly, we have generated fruit fly (Drosophila) models for many neurological and neuromuscular disorders that recapitulate key neuropathological phenotypes observed in patients. For example, Drosophila models the neurodegenerative diseases spinocerebellar ataxia type 1 (SCA1), Huntington’s, Parkinson’s and Alzheimer’s show late onset, progressive neuronal degeneration and disease-specific neuropathology. We use these Drosophila models as a discovery tool: together with state-of-the-art robotic instrumentation, they allow us to carry out high-throughput, genome-wide genetic screens to identify genetic modifiers and therapeutic targets—genome-scale screens in vivo are possible in Drosophila but not feasible using mouse models. These genetic approaches are integrated with human and model system -omic datasets. Network analyses allows us to nominate highly validated targets for in-depth studies using mice and human neurons.
In sum, we use a multidisciplinary, cross-species approach for comparative analysis of modifier genes and pathogenic mechanisms. Our goal is to identify therapeutic opportunities that may be applied to more than one neurological disorder.
Websites
Selected Publications
- Rousseaux MWC, Vázquez-Vélez GE, Al-Ramahi I,(...), Elledge SJ, Liu Z, Botas J, Zoghbi HY "A Druggable Genome Screen Identifies Modifiers of a-Synuclein Levels via a Tiered Cross-Species Validation Approach.." J Neurosci.. 2019;38:9286-9301.
- Al-Ramahi I, Lu B, Di Paola S, Pang K, de Haro M, (...), Liu Z, Medina DL, Botas J "High-Throughput Functional Analysis Distinguishes Pathogenic, Nonpathogenic, and Compensatory Transcriptional Changes in Neurodegeneration." Cell Syst.. 2018;7:28-40.e4..
- Al-Ramahi I, Giridharan SSP, Chen YC, Patnaik S, (...), Weisman LS, Botas J, Marugan JJ "Inhibition of PIP4Kgamma ameliorates the pathological effects of mutant huntingtin protein.." Elife. 2017;6:e29123.
- Rousseaux MW, de Haro M, Lasagna-Reeves CA, De Maio A, (...), Westbrook TF, Troncoso JC, Botas J, Zoghbi HY "TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau.." Elife. 2016;5:e19809.
- Lasagna-Reeves CA, de Haro M, Hao S, Park J, Rousseaux MW, Al-Ramahi I, (...), Tang J, Botas J, Zoghbi HY "Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model." Neuron. 2016;92:407-418.
- Bouché V, Espinosa AP, Leone L, Sardiello M, Ballabio A, Botas J "Drosophila Mitf regulates the V-ATPase and the lysosomal-autophagic pathway.." Autophagy. 2016;12:484-98.
- Park J, Al-Ramahi I, Tan Q, Mollema N, Diaz-Garcia JR, Gallego-Flores T, Lu HC, Lagalwar S, Duvick L, Kang H, Lee Y, Jafar-Nejad P, Sayegh LS, Richman R, Liu X, Gao Y, Shaw CA, Arthur JS, Orr HT, Westbrook TF, Botas J, Zoghbi HY "RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1." Nature. 2013 Jun 20;498(7454):325-31. Pubmed PMID: 23719381
- Lu B, Al-Ramahi I, Valencia A, Wang Q, Berenshteyn F, Yang H, Gallego-Flores T, Ichcho S, Lacoste A, Hild M, Difiglia M, Botas J, Palacino J "Identification of NUB1 as a suppressor of mutant Huntingtin toxicity via enhanced protein clearance." Nat Neurosci. 2013 May;16(5):562-70. Pubmed PMID: 23525043
- de Haro M, Al-Ramahi I, Jones KR, Holth JK, Timchenko LT, Botas J "Smaug/SAMD4A Restores Translational Activity of CUGBP1 and Suppresses CUG-Induced Myopathy." PLoS Genet. 2013 Apr;9(4):e1003445. Pubmed PMID: 23637619
- Branco J, Al-Ramahi I, Ukani L, Pérez AM, Fernandez-Funez P, Rincón-Limas D, Botas J "Comparative analysis of genetic modifiers in Drosophila points to common and distinct mechanisms of pathogenesis among polyglutamine diseases." Hum Mol Genet. 2008 Feb 1;17(3):376-90. Pubmed PMID: 17984172
- Romero E, Cha GH, Verstreken P, Ly CV, Hughes RE, Bellen HJ, Botas J "Suppression of neurodegeneration and increased neurotransmission caused by expanded full-length huntingtin accumulating in the cytoplasm." Neuron. 2008 Jan 10;57(1):27-40. Pubmed PMID: 18184562
- Al-Ramahi I, Pérez AM, Lim J, Zhang M, Sorensen R, de Haro M, Branco J, Pulst SM, Zoghbi HY, Botas J "dAtaxin-2 mediates expanded Ataxin-1-induced neurodegeneration in a Drosophila model of SCA1." PLoS Genet. 2007 Dec 28;3(12):e234. Pubmed PMID: 18166084
- Sofola OA, Jin P, Qin Y, Duan R, Liu H, de Haro M, Nelson DL, Botas J "RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS." Neuron. 2007 Aug 16;55(4):565-71. Pubmed PMID: 17698010
- Kaltenbach LS, Romero E, Becklin RR, Chettier R, Bell R, Phansalkar A, Strand A, Torcassi C, Savage J, Hurlburt A, Cha GH, Ukani L, Chepanoske CL, Zhen Y, Sahasrabudhe S, Olson J, Kurschner C, Ellerby LM, Peltier JM, Botas J, Hughes RE "Huntingtin interacting proteins are genetic modifiers of neurodegeneration." PLoS Genet. 2007 May 11;3(5):e82. Pubmed PMID: 17500595
- Lam YC, Bowman AB, Jafar-Nejad P, Lim J, Richman R, Fryer JD, Hyun ED, Duvick LA, Orr HT, Botas J, Zoghbi HY "ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology." Cell. 2006 Dec 29;127(7):1335-47. Pubmed PMID: 17190598
- Fernandez-Funez P, Nino-Rosales ML, de Gouyon B, She WC, Luchak JM, Martinez P, Turiegano E, Benito J, Capovilla M, Skinner PJ, McCall A, Canal I, Orr HT, Zoghbi HY, Botas J "Identification of genes that modify ataxin-1-induced neurodegeneration." Nature. 2000 Nov 2;408(6808):101-6. Pubmed PMID: 11081516
- Botas J, Moscoso del Prado J, García-Bellido A "Gene-dose titration analysis in the search of trans-regulatory genes in Drosophila.." EMBO J.. 1982;1(3):307-10. Pubmed PMID: 7188185
- Cukier HN, Perez AM, Collins AL, Zhou Z, Zoghbi HY, Botas J "Genetic modifiers of MeCP2 function in Drosophila.." PLoS Genet.. 2008;4(9):e1000179. Pubmed PMID: 18773074
- Capovilla M, Botas J "Functional dominance among Hox genes: repression dominates activation in the regulation of Dpp.." Development. 1998 Dec;125(24):4949-57. Pubmed PMID: 9811579
- Miller JP, Yates BE, Al-Ramahi I, Berman AE, Sanhueza M, Kim E, de Haro M, Degiacomo F, Torcassi C, Holcomb J, Gafni J, Mooney SD, Botas J, Ellerby LM, Hughes RE "A Genome-Scale RNA-Interference Screen Identifies RRAS Signaling as a Pathologic Feature of Huntington's Disease.." PLoS Genet.. 2012 Nov;8(11):e1003042. Pubmed PMID: 23209424
- Sofola OA, Jin P, Botas J, Nelson DL "Argonaute-2-dependent rescue of a Drosophila model of FXTAS by FRAXE premutation repeat.." Hum. Mol. Genet.. 2007 Oct 1;16(19):2326-32. Pubmed PMID: 17635840
- Bergman CM, Pfeiffer BD, Rincón-Limas DE, Hoskins RA, Gnirke A, Mungall CJ, Wang AM, Kronmiller B, Pacleb J, Park S, Stapleton M, Wan K, George RA, de Jong PJ, Botas J, Rubin GM, Celniker SE "Assessing the impact of comparative genomic sequence data on the functional annotation of the Drosophila genome.." Genome Biol.. 2002;3(12):RESEARCH0086. Pubmed PMID: 12537575
- Al-Ramahi I, Lam YC, Chen HK, de Gouyon B, Zhang M, Pérez AM, Branco J, de Haro M, Patterson C, Zoghbi HY, Botas J "CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation.." J. Biol. Chem.. 2006 Sep 8;281(36):26714-24. Pubmed PMID: 16831871
- Botas J, Auwers L "Chromosomal binding sites of Ultrabithorax homeotic proteins.." Mech. Dev.. 1996 May;56(41276):129-38. Pubmed PMID: 8798153
- Rincón-Limas DE, Lu CH, Canal I, Calleja M, Rodríguez-Esteban C, Izpisúa-Belmonte JC, Botas J "Conservation of the expression and function of apterous orthologs in Drosophila and mammals.." Proc. Natl. Acad. Sci. U.S.A.. 1999 Mar 2;96(5):2165-70. Pubmed PMID: 10051612
- Lu CH, Rincón-Limas DE, Botas J "Conserved overlapping and reciprocal expression of msh/Msx1 and apterous/Lhx2 in Drosophila and mice.." Mech. Dev.. 2000 Dec;99(41276):177-81. Pubmed PMID: 11091089
- Botas J "Control of morphogenesis and differentiation by HOM/Hox genes.." Curr. Opin. Cell Biol.. 1993 Dec;5(6):1015-22. Pubmed PMID: 7907490
- Capovilla M, Brandt M, Botas J "Direct regulation of decapentaplegic by Ultrabithorax and its role in Drosophila midgut morphogenesis.." Cell. 1994 Feb 11;76(3):461-75. Pubmed PMID: 7906203
- Capovilla M, Kambris Z, Botas J "Direct regulation of the muscle-identity gene apterous by a Hox protein in the somatic mesoderm.." Development. 2001 Apr;128(8):1221-30. Pubmed PMID: 11262224
- Botas J "Drosophila researchers focus on human disease.." Nat. Genet.. 2007 May;39(5):589-91. Pubmed PMID: 17460691
- Vachon G, Cohen B, Pfeifle C, McGuffin ME, Botas J, Cohen SM "Homeotic genes of the Bithorax complex repress limb development in the abdomen of the Drosophila embryo through the target gene Distal-less.." Cell. 1992 Oct 30;71(3):437-50. Pubmed PMID: 1358457
- Morata G, Botas J, Kerridge S, Struhl G "Homeotic transformations of the abdominal segments of Drosophila caused by breaking or deleting a central portion of the bithorax complex.." J Embryol Exp Morphol. 1983 Dec;78:319-41. Pubmed PMID: 6420494
- Zhang N, Li B, Al-Ramahi I, Cong X, Held JM, Kim E, Botas J, Gibson BW, Ellerby LM "Inhibition of Lipid Signaling Enzyme Diacylglycerol Kinase {epsilon} Attenuates Mutant Huntingtin Toxicity.." J. Biol. Chem.. 2012 Jun 15;287(25):21204-13. Pubmed PMID: 22511757
- Chen HK, Fernandez-Funez P, Acevedo SF, Lam YC, Kaytor MD, Fernandez MH, Aitken A, Skoulakis EM, Orr HT, Botas J, Zoghbi HY "Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1.." Cell. 2003 May 16;113(4):457-68. Pubmed PMID: 12757707
- Rodriguez-Esteban C, Schwabe JW, Peña JD, Rincon-Limas DE, Magallón J, Botas J, Izpisúa Belmonte JC "Lhx2, a vertebrate homologue of apterous, regulates vertebrate limb outgrowth.." Development. 1998 Oct;125(20):3925-34. Pubmed PMID: 9735354
- Miller JP, Holcomb J, Al-Ramahi I, de Haro M, Gafni J, Zhang N, Kim E, Sanhueza M, Torcassi C, Kwak S, Botas J, Hughes RE, Ellerby LM "Matrix metalloproteinases are modifiers of huntingtin proteolysis and toxicity in Huntington's disease.." Neuron. 2010 Jul 29;67(2):199-212. Pubmed PMID: 20670829
- de Haro M, Al-Ramahi I, De Gouyon B, Ukani L, Rosa A, Faustino NA, Ashizawa T, Cooper TA, Botas J "MBNL1 and CUGBP1 modify expanded CUG-induced toxicity in a Drosophila model of myotonic dystrophy type 1.." Hum. Mol. Genet.. 2006 Jul 1;15(13):2138-45. Pubmed PMID: 16723374
- Zoghbi HY, Botas J "Mouse and fly models of neurodegeneration.." Trends Genet.. 2002 Sep;18(9):463-71. Pubmed PMID: 12175807
- Irvine KD, Botas J, Jha S, Mann RS, Hogness DS "Negative autoregulation by Ultrabithorax controls the level and pattern of its expression.." Development. 1993 Jan;117(1):387-99. Pubmed PMID: 7900988
- Shirasaki DI, Greiner ER, Al-Ramahi I, Gray M, Boontheung P, Geschwind DH, Botas J, Coppola G, Horvath S, Loo JA, Yang XW "Network organization of the huntingtin proteomic interactome in Mammalian brain.." Neuron. 2012 Jul 12;75(1):41-57. Pubmed PMID: 22794259
- Kadener S, Villella A, Kula E, Palm K, Pyza E, Botas J, Hall JC, Rosbash M "Neurotoxic protein expression reveals connections between the circadian clock and mating behavior in Drosophila.." Proc. Natl. Acad. Sci. U.S.A.. 2006 Sep 5;103(36):13537-42. Pubmed PMID: 16938865
- Bendall AJ, Rincón-Limas DE, Botas J, Abate-Shen C "Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity.." Differentiation. 1998 Jul;63(3):151-7. Pubmed PMID: 9697309
- Qi ML, Tagawa K, Enokido Y, Yoshimura N, Wada Y, Watase K, Ishiura S, Kanazawa I, Botas J, Saitoe M, Wanker EE, Okazawa H "Proteome analysis of soluble nuclear proteins reveals that HMGB1/2 suppress genotoxic stress in polyglutamine diseases.." Nat. Cell Biol.. 2007 Apr;9(4):402-14. Pubmed PMID: 17384639
- Holth JK, Bomben VC, Reed JG, Inoue T, Younkin L, Younkin SG, Pautler RG, Botas J, Noebels JL "Tau loss attenuates neuronal network hyperexcitability in mouse and Drosophila genetic models of epilepsy.." J. Neurosci.. 2013 Jan 23;33(4):1651-9. Pubmed PMID: 23345237
- Tsuda H, Jafar-Nejad H, Patel AJ, Sun Y, Chen HK, Rose MF, Venken KJ, Botas J, Orr HT, Bellen HJ, Zoghbi HY "The AXH domain of Ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/Senseless proteins.." Cell. 2005 Aug 26;122(4):633-44. Pubmed PMID: 16122429
- Chan SK, Jaffe L, Capovilla M, Botas J, Mann RS "The DNA binding specificity of Ultrabithorax is modulated by cooperative interactions with extradenticle, another homeoprotein.." Cell. 1994 Aug 26;78(4):603-15. Pubmed PMID: 7915199
- Eldon E, Kooyer S, D'Evelyn D, Duman M, Lawinger P, Botas J, Bellen H "The Drosophila 18 wheeler is required for morphogenesis and has striking similarities to Toll.." Development. 1994 Apr;120(4):885-99. Pubmed PMID: 7600965
- Sofola O, Sundram V, Ng F, Kleyner Y, Morales J, Botas J, Jackson FR, Nelson DL "The Drosophila FMRP and LARK RNA-binding proteins function together to regulate eye development and circadian behavior.." J. Neurosci.. 2008 Oct 8;28(41):10200-5. Pubmed PMID: 18842880
- Rincón-Limas DE, Lu CH, Canal I, Botas J "The level of DLDB/CHIP controls the activity of the LIM homeodomain protein apterous: evidence for a functional tetramer complex in vivo.." EMBO J.. 2000 Jun 1;19(11):2602-14. Pubmed PMID: 10835358
- Lilly B, O'Keefe DD, Thomas JB, Botas J "The LIM homeodomain protein dLim1 defines a subclass of neurons within the embryonic ventral nerve cord of Drosophila.." Mech. Dev.. 1999 Nov;88(2):195-205. Pubmed PMID: 10534618
- Stanley H, Botas J, Malhotra V "The mechanism of Golgi segregation during mitosis is cell type-specific.." Proc. Natl. Acad. Sci. U.S.A.. 1997 Dec 23;94(26):14467-70. Pubmed PMID: 9405636
- Fernández-Fúnez P, Lu CH, Rincón-Limas DE, García-Bellido A, Botas J "The relative expression amounts of apterous and its co-factor dLdb/Chip are critical for dorso-ventral compartmentalization in the Drosophila wing.." EMBO J.. 1998 Dec 1;17(23):6846-53. Pubmed PMID: 9843490
- Onur TS, Laitman A, Zhao H, Keyho R, Kim H, Wang J, Mair M, Wang H, Li L, de Haro M, Wan Y-W, Allen G, Lu B, Al-Ramahi I, Liu Z, Botas J "Downregulation of glial genes involved in synaptic function mitigates Huntington’s disease pathogenesis." Elife. 2021;10:e64564. Pubmed PMID: 33871358
- Kim YW, Al-Ramahi I, Koire A, Wilson SJ, Konecki DM, Mota S, Soleimani S, Botas J, Lichtarge O "Harnessing the paradoxical phenotypes of APOE ɛ2 and APOE ɛ4 to identify genetic modifiers in Alzheimer's disease." Alzheimers Dement.. 2021;17:831-846. Pubmed PMID: 33576571
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