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J. Paul Taylor, M.D., Ph.D.

Assistant Professor
Department of Neurology 3 W. Gates Building
Office (215) 573-1147
Fax (215) 573-1153
email:  jpt@mail.med.upenn.edu

For more information about the Taylor Lab, please click here

RESEARCH INTERESTS

RESEARCH TECHNIQUES

RESEARCH SUMMARY

Deposition of misfolded and aggregated proteins is a pathological hallmark of many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, prion diseases, and the polyglutamine diseases. Our understanding of the molecular basis of neurodegeneration has advanced significantly with recent identification of the mutations responsible for familial cases of several of these diseases. In some instances, gain-of-function mutations lead to conformational changes that promote protein aggregation. In other instances, loss-of-function the mutations occur in the machinery responsible for clearing defective, aggregation-prone proteins. Thus, a unifying hypothesis has emerged regarding the underlying mechanism at work in these "proteinopathies". Specifically, this hypothesis asserts that certain proteins are vulnerable to misfolding into pathological conformations that assemble into aggregates and acquire neurotoxic properties. According to this view, neurodegenerative disease ensues when the accumulation of neurotoxic proteins exceed the cell's capacity for disposing of them or when neurotoxic proteins evade quality-control surveillance altogether.

A prediction of this hypothesis is that it may be possible to develop parallel approaches to treatment based on a better grasp on the targets of neurotoxic, aggregation-prone proteins and greater insight into the normal cellular mechanisms for disposing unwanted proteins. Identifying the primary targets of neurotoxic proteins and developing target-based therapeutics are the focus of our research. Toward these ends, we have undertaken molecular and pathological analyses of cell culture and Drosophila models of neurodegenerative diseases. In addition, we are pursuing high throughput screens to identify compounds with therapeutic potential for these diseases.

REFERENCES:

Sumner, C.J., Huynh, T., Markowitz, J.A., Coovert, D.D., Schussler, K., Jarecki, J., Burghes, A.H.M., Taylor, J.P. and Fischbeck, K.H. (2003) Valproic acid increases SMN levels in spinal muscular atrophy patient cells. Ann. Neurol. 54(5), 647-654.

Piccioni, F., Romano, B., Fischbeck, K.H. and Taylor, J.P. (2004) A screen for drugs that protect against the toxicity of polyglutamine-expanded androgen receptor. Hum. Molec. Genet . 13(4), 437-446.

Zeng, X-C., Bhasin, S., Wu, X., Lee, J-G., Maffi, S., Nichols, C.J., Taylor , J.P. , Greene, L.E. and Eisenberg, E. (2004) Hsp70 dynamics in vivo: effect of heat shock and protein aggregation. J. Cell Sci. 117(21), 4991-5000.

Subramony, S.H., May, W., Lynch D.R., Gomez, C., Fischbeck, K.H., Hallett, M., Taylor , J.P. , Wilson , R.L., Ashizawa, T. and the Cooperative Ataxia Group.  Measuring Friedreich's ataxia: inter-rater reliability of a neurologic rating scale.   Neurology 64, 1261-1263.

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