During the past 10 years, Dr. Petsko has pursued groundbreaking research not only on how proteins work, but how they are related to the causes of neurodegenerative diseases. Using the techniques of genetics, structural biology, and structure-guided drug discovery, his laboratory is able to identify, validate, and exploit novel targets for the treatment of age-related neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Lou Gehrig’s diseases.
Alzheimer’s disease starts when a protein that should be folded up properly for normal brain functioning instead is aberrantly processed, misfolds and then aggregates. Interestingly, diseases that affect other parts of the brain also show similar aggregates of misfolded proteins. This suggests that a therapeutic approach developed for Alzheimer’s might also be used to treat many neurological diseases. With this in mind, the Petsko lab has been collaborating with that of Dr. Scott Small of Columbia University and Dr. Dagmar Ringe of Brandeis University on the development of drugs that will route the Alzheimer’s protein away from the subcellular compartments where misprocessing and aggregation begin. Two of the compounds, pharmacological chaperones for the retromer protein complex, have shown good results in neurons in cell culture, and are now being tested in mouse models of Alzheimer’s disease. The figure below shows that these compounds lower the level of the pathological hallmark of Parkinson’s is the accumulation in nerve cells of dense clumps of another aggregated protein, called alpha-synuclein.
Alpha-synuclein does not normally form such aggregates in healthy brain cells, so identifying the process that triggers its aggregation in the early stages of Parkinson’s disease may provide a therapeutic opportunity. Focusing on what might be nucleating the formation of the synuclein aggregates, The Petsko and Ringe labs identified an enzyme that clipped synuclein, forming rapidly aggregating fragments, and showed that inhibiting this enzyme with a specific drug blocked the formation of the synuclein fragments, thereby preventing or delaying the formation of the aggregates that these fragments promote. Two such inhibitors are now being tested in several rodent models of Parkinson’s disease. The figure below shows, from left to right, that the fragment aggregates much more rapidly than the full-length protein; that it is formed when full-length synuclein is incubated with the appropriate protease, but is not formed when that protease is inhibited; and that inhibition of the protease can rescue neurons from the toxicity of synuclein in a dose-dependent manner.
Finally, Dr. Petsko’s lab has been developing a novel gene therapy for amyotrophic lateral sclerosis (Lou Gehrig’s disease or ALS), starting with studies of the toxicity of ALS-related proteins in yeast. By overexpressing the human UPF1 gene, which codes for a protein that is involved in a cellular pathway called nonsense mediated decay, the lab has succeeded in completely blocking the death of motor neurons in cell culture models of ALS. With the help of several collaborators, they have been able to engineer a virus to carry this gene into the spinal motor neurons, and are now testing the therapy on rat and mouse models of ALS to see if it can retard and/or halt the progression of the disease. The figure on the left below shows hUPF1 and its yeast homologue ECM32 are able to suppress the severe toxicity of the familial ALS gene FUS/TLS in yeast; they also suppress the toxicity in yeast of another ALS gene, TDP-43 (not shown). The figure on the right shows that the suppression of TDP-43 toxicity (and that of FUS, which is not shown) also works in a motor neuron cell model of ALS.
The long-term goals of the lab are to see our treatments tested in people. This means Phase I clinical trials for toxicity; Phase II clinical trials for efficacy; and eventually Phase III clinical trials leading to approved use of the treatment for a neurodegenerative disease. While we suspect that our treatments, if they are successful at all, are more likely to be preventive than disease-modifying, we still have some hope that they may do both. At the very least, we hope that the testing of these therapeutics in both models of disease and, eventually, actual human patients, may provide new insights into the mechanisms of these disorders and lead to new approaches to their cure.
The laboratory has benefitted from generous support from the National Institutes of Health, the McKnight Endowment for Neuroscience, the Ellison Medical Research Foundation, the Michael J. Fox Foundation, and the Fidelity Biosciences Research Initiative, as well as from a number of private benefactors, including Robert and Christina Dow.