Many neurodegenerative diseases are characterized by the early loss of select groups of cells in the brain, followed only later by more widespread degeneration. Understanding the cause of the enhanced vulnerability displayed by select cell groups may point towards the root causes of these diseases and lead to novel therapeutic targets. Professor Myriam Heiman’s lab studies the selective vulnerability and pathophysiology seen in two neurodegenerative diseases of the basal ganglia, Huntington’s disease and Parkinson’s disease.
The easily recognizable ravages of Huntington’s disease and Parkinson’s disease on normal motor control reflect the loss of either dopamine-producing cells (Parkinson’s disease) or dopamine-receiving cells (Huntington’s disease) in the brain. Until fairly recently, patients afflicted with these diseases would be diagnosed mainly by these abnormal motor behaviors. However, it was not known why a patient was afflicted; no usually suspected causes existed. The last twenty years have seen remarkable progress in the study of the causes of both diseases: it is now known which gene is altered in all patients with Huntington’s disease, and many genes have been implicated in Parkinson’s disease through human genetic studies. In the case of Huntington’s disease, detection of alterations in one gene, huntingtin, now serves as the definitive diagnostic tool. However, even in this one-gene disease, the full functional consequences of huntingtin gene alterations that lead to cell death are not yet understood.
Several fundamental questions arise from the knowledge that has poured forth from genetic and molecular studies of these diseases in human patients and mouse models: why do dopamine-producing cells and dopamine-receiving cells exhibit the greatest vulnerability in Parkinson’s disease and Huntington’s disease, respectively, even though the genes linked to these diseases are expressed in so many different types of cells? What do the products of genes implicated in Huntington’s disease and Parkinson’s disease do, or fail to do, in patients with these diseases? What is the influence of the normal aging process on the fate of the affected cells, and why do these diseases mostly affect older adults? Finally, in the case of Parkinson’s disease, what happens in the ravaged brain upon administration of drugs used to treat this disease – why do drugs lose their efficacy over time and have the side effects that they do?
To address these questions, the lab is utilizing a novel methodology termed Translating Ribosome Affinity Purification (TRAP). This methodology allows for the profiling of any genetically-defined cell type in any tissue: gene regulatory elements are co-opted to drive expression of a transgene that causes the incorporation of an affinity tag on translating ribosomes. Tagged ribosomes can be purified, along with all the messenger RNAs (mRNAs) they are reading. These mRNAs can then be analyzed to reveal the complete pattern of protein translation in any given cell at any given time. By combining the TRAP methodology with mouse models of Huntington’s disease and Parkinson’s disease, the lab hopes to understand the early molecular changes that eventually lead to cell death in these diseases.
Myriam Heiman received her Ph.D. in Biology from the Johns Hopkins University and her postdoctoral training in the laboratory of Paul Greengard at the Rockefeller University. In 2011, she joined the Broad Institute, the Department of Brain and Cognitive Sciences, and the Picower Institute for Learning and Memory at MIT.
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