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Molecular mechanisms of pathogenesis in neurodegenerative diseases; comparative molecular genetics of development in
Drosophila and vertebrates
We use Drosophila as a model system to investigate the genetic control of normal development and the
mechanisms of pathogenesis involved in human disease. Then, we use cross-species approaches to validate in vertebrate model
systems the findings obtained with Drosophila. Two major projects are the focus of research in our laboratory.
- Comparative analysis of normal development
We are investigating the conservation of function and regulation of gene hierarchies playing key roles during limb development in
insects and vertebrates. We use molecular genetic, transgenic and genomic approaches to investigate the conserved and distinct
functions of LIM/homeobox genes controlling dorso-ventral and proximo-distal limb patterning.
- Drosophila models of neurodegenerative diseases
During the past decade many genes triggering neurodegenerative diseases have been identified. We learned that many of these diseases
are caused by gain of function mutations and/or impaired proteolysis of the respective proteins. Among these proteins are huntingtin
(Huntington's disease), α-synuclein (Parkinson's disease) and the tau and amyloid precursor proteins (in Alzheimer's). 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 neurodegenerative diseases including
spinocerebellar ataxia type 1 (SCA1), Huntington's, Parkinson's and Alzheimer's diseases. These fly models recapitulate the neuronal
phenotypes observed in patients, including the formation of protein aggregates, the accumulation of chaperones and ubiquitin-
proteolytic pathway components in these aggregates, and the progressivity of the degenerative phenotype. We also developed assays
that allow rapid, genome-wide genetic screenings aimed to identify the genes and pathways involved in pathogenesis. 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. We are using similar genetic approaches to identify novel suppressors of
degeneration in the Huntington's, Parkinson's and Alzheimer's fly models, and to define common and disease-specific genes involved
in pathogenesis.
Selected Publications
Fernández-Fúnez P, Lu C-H, Rincón-Limas DE, García-Bellido A, Botas J
(1998) The relative expression amounts of apterous and its co-factor dLdb/Chip are critical for dorso-ventral
compartmentalization in the Drosophila wing. EMBO Journal 17:6846-6853.
Rodríguez-Esteban C, Schwabe JWR, De La Peña J, Rincón-Limas DE, Magallón J,
Botas J, Izpisúa-Belmonte JC (1998) Lhx2, a vertebrate homologue of apterous, regulates
vertebrate limb outgrowth. Development 125:3925-3934.
Rincón-Limas DE, Lu C-H, Canal I, Calleja M, Rodríguez-Esteban C, Izpisúa-Belmonte JC,
Botas J (1999) Conservation of the expression and function of apterous orthologs in Drosophila and mammals.
Proceedings of the National Academy of Sciences U.S.A. 96:2165-2170.
Rincón-Limas DE, Lu C-H, Canal I, Botas J (2000) The level of dLdb/Chip controls the activity of the
LIM homeodomain protein Apterous: evidence for a functional tetramer complex in vivo. EMBO Journal 19:2602-2614.
Fernández-Fúnez P, Niño-Rosales ML, de Gouyon B, She W-C, Luchack JM, Martinez P, 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.
Capovilla M, Kambris Z, Botas J (2001) Direct regulation of the muscle-identity gene apterous by a Hox
protein in the somatic mesoderm. Development 128:1221-1230.
Zoghbi HY, Botas J (2002) Mouse and fly models of neurodegeneration. Trends in Genetics 18:463-471.
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 (2002)
Assessing the impact of comparative genomic sequence data on the functional annotation of the Drosophila genome.
Genome Biology 3: RESEARCH0086.1-0086.20.
Chen H-K, Fernández-Fúnez P, Acevedo SF, Lam YC, Kaytor MD, Fernandez MH, Aitken A, Skoulakis
EMC, Orr HT, Botas J, Zoghbi HY (2003) Interaction of akt-phosphorylated ataxin-1 with 14-3-3 mediates
neurodegeneration in spinocerebellar ataxia type 1. Cell 113:457-468.
Contact Information
- Juan Botas, Ph.D.
- Department of Molecular & Human Genetics
- Baylor College of Medicine
- One Baylor Plaza S944
- Houston, Texas 77030, U.S.A.
- Tel: (713) 798-5937
- Fax: (713) 798-5386
- E-mail: jbotas@bcm.edu
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