B.S., University of Madrid, 1980
Ph.D., University of Madrid, 1986
Postdoc, Stanford University Medical Center
During the past decade 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), alpha-synuclein (Parkinson disease) and the tau and amyloid precursor proteins (in Alzheimer's). 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?
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 the genes and pathways involved in pathogenesis that are not practical using other animal models. We have shown the validity of this approach using a Drosophila model of SCA1. A screen for genetic modifiers of SCA1-induced neurodegeneration produced a variety of suppressors and enhancers of the SCA1 phenotype many of which function in pathways not previously known to be involved in neurodegeneration (Nature 408: 101-6, 2000; Cell 113: 457-68, 2003).
We are using similar genetic approaches to identify novel genetic modifiers of pathogenesis in Drosophila models of Rett Syndrome, Huntington’s disease, Alzheimer’s disease and Myotonic dystrophy. We are particularly interested in behavioral phenotypes caused by neuronal dysfunction in defined neuronal circuits, and we established assays that allow us to estimate the impact of genetic modifiers at the molecular, cellular and behavioral levels.
SELECTED PUBLICATIONS:
1. 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: 376-390.
2. 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: 27-40.
3. 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: e234.
4. 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: 565-571.
5. Sofola OA, Jin P, Botas J, Nelson DL (2007). Argonaute-2-dependent rescue of a Drosophila model of FXTAS by FRAXE premutation repeat. Hum. Mol. Genet. 16: 2326-2332.
6. 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: e82.
7. Qi ML, Tagawa K, Enokido Y, Yoshimura N, Wada Y, Watase K, Ishiura S, Kanazawa I, Botas J, Saitoe M, Wanker EE, Okazawa H (2007). Proteome analysis of soluble nuclear proteins reveals that HMGB1/2 suppress genotoxic stress in polyglutamine diseases. Nat. Cell Biol. 9: 402-414.
8. Botas J (2007). Drosophila researchers focus on human disease. Nat. Genet. 39: 589-591.
9. 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: 1335-1347.
10. 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: 101-106.
For more publications, see listing on Pub Med.
CONTACT INFORMATION:
Juan Botas, Ph.D.
Department of Molecular and Human Genetics
Baylor College of Medicine
One Baylor Plaza
Houston, Texas 77030, U.S.A.
Telephone: 713-798-5397
Fax: 713-798-8142
E-mail: