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 toward the root causes of these diseases and lead to novel therapeutic targets. Myriam Heiman's lab uses the mammalian basal ganglia as a model for selective vulnerability and pathophysiology in neurodegenerative disease.
To better understand the cell-type specific basis of selective vulnerability in disease, the Heiman 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 neurodegenerative disease, the lab hopes to understand the early molecular changes that eventually lead to cell death in disease.
I. Neuronal profiling of normal aging
A major unresolved question in the study of neuronal aging is why most neurodegenerative diseases only reveal themselves late in life. The Heiman lab is investigating how the molecular profiles of different populations of cells in the nervous system change during normal aging. Results from these studies will be used to investigate the molecular basis of neuronal longevity, and how young neurons protect against pathology, using mouse models of neurodegenerative diseases.
II. Neuronal profiling in mouse models of Huntington’s disease
A fascinating example of enhanced cell-type specific disease vulnerability occurs in Huntington’s disease (HD), a monogenic neurodegenerative disease caused by expansion of CAG (glutamine-encoding) trinucleotide repeats in the huntingtin gene. In HD, medium-size spiny neurons of the striatum are dramatically affected, and in late stages of this disease, most medium-spiny neurons are lost. Paradoxically, the huntingtin gene itself is expressed from birth in most cells of the body. Thus, medium-spiny neurons may express other factors that make them especially susceptible to death in HD (or they may fail to express factors that would make them more resistant). To identify such susceptibility factors, the Heiman lab is using TRAP to compare the molecular profiles of more resistant and more vulnerable cell populations in HD. The aim of this research is to identify protective factors that may alter the course of Huntington’s disease progression and reveal insights into medium-spiny neuron physiology.
III. Neuronal profiling in mouse models of Parkinson’s disease
A related focus in the lab is aimed at understanding how long-term adaptations occur in the brain in response to the loss of a key neurotransmitter, dopamine. Specifically, the motor symptoms of Parkinson’s disease (PD) – including resting tremor, rigidity, akinesia, and postural instability – are seen upon dopamine depletion in the brain, resultant from the death of dopamine-producing cells in the substantia nigra. A standard treatment for PD is administration of levodopa, which can be converted to dopamine, and which works well in the short-term to relieve symptoms. However, interestingly, over the long-term, patients receiving levodopa develop debilitating side effects and, over time, this drug loses its efficacy. In a collaborative project, the lab is investigating the levodopa-induced changes that occur in one of the major cell classes that levodopa acts upon: medium-spiny neurons in the striatum. The goal of this project is to identify the molecular basis of levodopa-induced side effects, which may ultimately lead to therapeutic targets for the long-term treatment of a Parkinsonian state.
The mosaic nature of the brain reveals itself in the course of diseases, including Huntington’s and Parkinson’s disease, which preferentially strike particular cell types. The Heiman lab is using cell-type specific profiling to identify the molecular basis of this differential vulnerability, in the hope of making progress toward new disease therapeutics, and continuing to unravel the complexity of the mammalian brain.