Juan Botas, Ph.D.
Juan Botas, Ph.D.
Molecular and Human Genetics
Baylor College of Medicine
Houston, TX, US
Molecular and Cellular Biology
Baylor College of Medicine
Houston, Texas, United States
- 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
- Comparative analysis of pathogenic mechanisms in neurodegenerative disorders
- Screens for common 'drugable' targets
Professional StatementDuring 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 disease, PD) and the tau and amyloid precursor proteins (in Alzheimer's 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.
- 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 June 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 April ; 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 February 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 January 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 December 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 August 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 December 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 November 2; 408 (6808): 101-6. Pubmed PMID: 11081516
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