Redirected Therapies for Neurodegenerative Diseases
Thursday, April 5, 2007
Presented by the Neurodegenerative Diseases Discussion Group
Organizer: Michael Wolfe, Harvard Medical School
The Neurodegenerative Diseases Discussion Group will focus broadly on the theme of neurodegenerative diseases in a highly interdisciplinary fashion. Meetings will focus on a single issue as it relates to neurodegenerative diseases in general including cell death, mitochondrial function, protein misfolding, glial cell function, motor neuron deficiencies, and synaptic integrity. In addition, each meeting will feature talks covering basic, clinical and translational aspects of research into neurodegenerative diseases.
HDAC Inhibition as a Potential Treatment for Huntington's Disease
Leslie Thompson, PhD
University of California, Irvine
Huntington's disease (HD) is a devastating late onset neurodegenerative disease with no known treatment or cure. Symptoms of this disease include a movement disorder, cognitive deficits and psychiatric disturbances. HD represents one of a growing number of polyglutamine (polyQ) repeat diseases that cause region-specific neuronal degeneration. Normal repeat Htt is primarily extranuclear; however, mutant Htt progressively accumulates in the nuclei of neurons, ultimately forming visible nuclear inclusions. A consequence of this nuclear accumulation of Htt appears to be the dysregulation of transcription, a relatively early event in HD. A growing number of studies suggest that altered activity of histone acetyltransferases (HATSs) and HistoneDeAcetylases (HDACs) may be involved in HD pathogenesis and may promote altered regulation of transcription. Several HAT proteins, which acetylate histones and other cellular proteins, are bound and inhibited by the mutant Huntingtin (Htt) protein. Blocking the action of the counteracting enzymes, HDACs, either through genetic or pharmacologic means, can suppress pathology. The specificity of HATs and HDACs in the pathogenic process of HD will be discussed. The application of these findings in cell culture models and Drosophila models to mouse models of HD supports the potential utility of "transcriptional therapy" as a future treatment option for patients.
Modulating and Inhibiting Intramebrane Proteolysis: Applications to Alzheimer's Disease, Cancer and Parasitic Diseases
Todd Golde, PhD
Mayo Clinic - Jacksonville
Presenilins (PSs) and signal peptide peptidase (SPP) are members of an intramembrane cleaving protease family of integral membrane proteins. PSs and SPPs are of great interest because of the unusual nature of their proteolytic cleavage, their normal physiologic roles, and their potential as therapeutic targets in such diverse disease settings as Alzheimer's disease (AD), cancer and parasitic diseases. Small molecule inhibitors and modulators of SPP and PSs have been identified and may therefore have utility as therapeutic agents in a variety of disease settings. The therapeutic potential of inhibition and modulation of these proteases will be presented with specific reference to AD, cancer, and malaria.
Farnesyl Transferase Inhibition as a Therapeutic Strategy Against Parkinson's Disease
Peter Lansbury, PhD
Harvard Medical School
Chief Scientific Officer, Link Medicine
Craig Justman, PhD
Farnesyl transferase inhibitors (FTIs) have been developed as cancer therapeutics, based on the finding that the oncogene product Ras requires farnesylation to be activated. Two FTIs are in advanced clinical trials for cancer. We discovered that UCH-L1, a protein that is linked to Parkinson's disease (PD), is also farnesylated in vivo. Furthermore, the farnesylated form of UCH-L1 plays a role in the degradation of alpha-synuclein, which has also been lined to PD. This talk will discuss the experimental evidence for these claims and explore the potential for FTIs to be used to slow the progression of