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Neurodegenerative disease models in Drosophila
As a neurologist and physician scientist, I have decided to dedicate my research to understanding the pathogenesis of Amyotrophic
Lateral Sclerosis (ALS) with the hope of developing a cure for this disease.
ALS, also known as Lou Gehrig’s disease, is a devastating neurodegenerative disorder caused by progressive loss of motor neuron function
in the brain and spinal cord. Eventually patients will not be able to stand or walk, get in or out of bed on their own, or use their hands and arms.
Difficulty swallowing and chewing impair the patient’s ability to eat normally and increase the risk of choking. Maintaining weight will then
become a problem. Because the disease usually does not affect cognitive abilities, patients are aware of their progressive loss of function and may
become anxious and depressed. Typically ALS is late-onset (between age 45 and 60) and progresses relatively fast (the average disease course is two
to five years). Currently, there are about 30,000 ALS patients in the U.S. Unfortunately, there is no primary therapy for ALS and the molecular and
cellular mechanisms of ALS pathogenesis are very poorly understood.
I firmly believe that modeling the disease in flies and mice is our only hope to understand the pathogenesis of ALS, and have therefore developed
a Drosophila ALS model. First, I started working on ALS8, a familial form of ALS. ALS8 is caused by a mutation in Vamp associated protein B (VAPB). We
have discovered that a novel hormone derived from VAPB is secreted into the blood and functions as a ligand for Eph receptors. Importantly, the ALS8 mutation
in VAP causes two different types of defects: first, it leads to reduced secretion of VAP, thereby abolishing its cell non-autonomous function as a hormone;
second, the mutant VAP protein causes an accumulation of the protein in the endoplasmic reticulum that creates an unfolded protein response, which may be toxic
to the cells. Both defects may synergize to produce the key features of ALS8 pathology. Interestingly, VAP protein levels are severely decreased in sporadic cases of ALS.
In addition, our ALS8 fly model phenocopies many of the common features of sporadic and familial ALS, including ubiquitinated inclusions, the UPR, and mitochondrial
degeneration, suggesting that VAP may also play a role in sporadic ALS cases.
Our studies are designed to provide a comprehensive assessment of the pathogenesis of ALS in flies, mice, and humans. Currently, we are working on 1) how a failure to
secrete VAP and a dysfunction of the Eph receptor or other candidate receptors contribute to ALS, 2) mechanisms of the secretion of VAP mediated by VAP interacting proteins,
3) establishing other ALS fly models.
Selected Publications
Takebayashi K, Takahashi S, Yokota C, Tsuda H, Nakanishi S, Asashima M, Kageyama R (1997) Conversion of ectoderm into a neural fate
by ATH-3, a vertebrate basic helix-loop-helix gene homologous to Drosophila proneural gene atonal. EMBO Journal
16:384-395.
Tsuda H, Takebayashi K, Nakanishi S, Kageyama R (1998) Structure and promoter analysis of Math3 gene, a mouse homolog of
Drosophila proneural gene atonal. Neural-specific expression by dual promoter elements. Journal of Biological Chemistry
273:6327-6333.
Nishimura M, Isaka F, Ishibashi M, Tomita K, Tsuda H, Nakanishi S, Kageyama R (1998) Structure, chromosomal locus, and promoter of
mouse Hes2 gene, a homologue of Drosophila hairy and Enhancer of split. Genomics 49:69-75.
Nakatani J, Mizuseki K, Tsuda H, Nakanishi S, Sasai Y (2000) Xenopus Xenf: an early endodermal nuclear factor that is
regulated in a pathway distinct from Sox17 and Mix-related gene pathways. Mechanisms of Development 91:81-89.
Tsuda H, Sasai N, Matsuo-Takasaki M, Sakuragi M, Murakami Y, Sasai Y (2002) Dorsalization of the neural tube by Xenopus tiarin,
a novel patterning factor secreted by the flanking nonneural head ectoderm. Neuron 33:515-528.
Tsuda H, Jafar-Nejad H, Patel AJ, Sun Y, Chen HK, Rose MF, Venken KJ, Botas J, Orr HT, Bellen HJ, Zoghbi HY (2005) The AXH domain of Ataxin-1
mediates neurodegeneration through its interaction with Gfi-1/Senseless proteins. Cell 122:633-644.
Tsuda H, Han SM, Yang Y, Tong C, Lin YQ, Mohan K, Haueter C, Zoghbi A, Harati Y, Kwan J, Miller MA, Bellen HJ (2008) The Amyotrophic Lateral Sclerosis 8 protein VAPB is cleaved,
secreted, and acts as a ligand for Eph receptors. Cell 133:963-977.
Contact Information
- Hiroshi Tsuda, M.D., Ph.D.
- Department of Molecular and Human Genetics
- Baylor College of Medicine
- One Baylor Plaza T630
- Houston, Texas 77030, U.S.A.
- Tel: (713) 798-8841
- Fax: (713) 798-3694
- E-mail: htsuda@bcm.edu
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