Gregory Petsko   Arthur J. Mahon Professor of Neuroscience

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For over 30 years Dr. Gregory Petsko and his colleague, Prof. Dagmar Ringe, have used protein crystallography, molecular biology, and genetics to probe the relationship between protein structure and function. Their research has been concerned with the three-dimensional structures and dynamics of proteins and their biochemical functions, with a particular focus on the structural basis for efficient enzymic catalysis; direct visualization of proteins in action by timeresolved protein crystallography; the evolution of new enzyme activities; and the biology of the quiescent state in eukaryotic cells.

During the past 10 years, Drs. Petsko and Ringe have pursued groundbreaking research not only on how proteins work, but how they are related to the causes of neurodegenerative diseases. They use the techniques of genetics, structural biology, and structure-guided drug discovery 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.

During the past 10 years, Drs. Petsko and Ringe have pursued groundbreaking research not only on how proteins work, but how they are related to the causes of neurodegenerative diseases.

Alzheimer’s disease starts when a protein that should be folded up properly for normal brain functioning instead 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, they have been collaborating with Dr. Scott Small of Columbia 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 their compounds have shown good results in neurons in cell culture, and are now being tested in mouse models of Alzheimer’s disease.

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, they identified an enzyme that clipped synuclein, forming rapidly aggregating fragments, and showed that inhibiting it 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.

Finally, they have been developing a novel gene therapy for amyotrophic lateral sclerosis (Lou Gehrig’s disease or ALS). By overexpressing the human UPF1 gene, which codes for a protein that is involved in a cellular pathway called nonsensemediated decay, they have 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 either retard or halt the progression of the disease.


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  • Translation to the Clinic of AAVrh.10-mediated Delivery to the CNS of the Apolipoprotein E2 Gene for Treatment of Alzheimer's Key Personnel 2015 -



full name

  • Dr. Gregory A. Petsko,

primary email



Primary Affiliation

  • Weill Cornell Medical College, Cornell University