Juan Botas, Ph.D.
Professor of Molecular and Human Genetics
Professor, Department of Molecular & Cellular Biology
B.S., University of Madrid, 1980
Ph.D., University of Madrid, 1986
Postdoc, Stanford University Medical Center
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 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. In spite of many significant advances in our understanding of these diseases, 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 mechanisms of pathogenesis? What are the genetic pathways and specific genes and proteins involved during disease progression? Can we identify new therapeutic targets?
To address these questions, we have generated Drosophila models for several 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 and Alzheimer’s show late onset, formation of protein aggregates, accumulation of chaperones and ubiquitin-proteolytic pathway components in these aggregates, and progressive neuronal degeneration. These Drosophila models of disease allow us to carry out rapid, genome-wide genetic screens to identify genetic modifiers and therapeutic targets—genome-scale screens are possible in Drosophila but not feasible using mouse models. We have shown the validity of this approach using Drosophila models of SCA1, HD, AD, PD, Myotonic dystrophy type 1 (DM1) etc. (see list of publications). A second interest of our research program is to exploit these Drosophila models for comparative analysis of modifier genes and pathogenic mechanisms to identify therapeutic opportunities that may be applied to more than one disease. These genetic approaches are integrated with transcriptomic and metabolomics analysis of disease models and human tissues. A third goal of our lab is to perform chemical screens using behavioral readouts to assess CNS function/ dysfunction resulting form neurological disorders.
- 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 (2013). RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1. Nature 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 (2013). Identification of NUB1 as a suppressor of mutant Huntington toxicity via enhanced protein clearance. Nat. Neurosci. 16(5): 562-70. PubMed PMID: 23525043
- de Haro M, Al-Ramahi I, Jones KR, Holth JK, Timchenko LT, Botas J (2013). Smaug/SAMD4A restores translational activity of CUGBP1 and suppresses CUG-induced myopathy. PLoS Genet. 9(4): e1003445. PubMed PMID: 23637619
- Branco J, Al-Ramahi I, Ukani L, Pérez AM, Fernandez-Funez P, Rincón-Limas D, Botas J (2008). Comparative analysis of genetic modifiers in Drosophila points to common and distinct mechanisms of pathogenesis among polyglutamine diseases. Hum. Mol. Genet. 17(3): 376-90. PubMed PMID: 17984172
- Romero E, Cha GH, Verstreken P, Ly CV, Hughes RE, Bellen HJ, Botas J (2008). Suppression of neurodegeneration and increased neurotransmission caused by expanded full-length huntingtin accumulating in the cytoplasm. Neuron 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 (2007). dAtaxin-2 mediates expanded Ataxin-1-induced neurodegeneration in a Drosophila model of SCA1. PLoS Genet. 3(12): e234. PubMed PMID: 18166084
- Sofola OA, Jin P, Qin Y, Duan R, Liu H, de Haro M, Nelson DL, Botas J (2007). RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS. Neuron 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 (2007). Huntingtin interacting proteins are genetic modifiers of neurodegeneration. PLoS Genet. 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 (2006). ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology. Cell 127(7): 1335-47. PubMed PMID: 17190598
- Fernandez-Funez P, Rosales MLN, de Gouyon B, She WC, Luchack J, Turiegano E, Benito J, Capovilla M, Skinner PJ, McCall A, Canal I, Orr HT, Zoghbi HY, Botas J (2000). Identification of genes that modify ataxin-1 induced neurodegeneration. Nature 408(6808): 101-6. PubMed PMID: 11081516
Juan Botas, Ph.D.
Department of Molecular and Human Genetics
Baylor College of Medicine
One Baylor Plaza, MS BCM225
Houston, TX, 77030, U.S.A.