HDSA Research News:   New clues to why striatal neurons are preferentially damaged in HD

HDSA-supported study also suggests activation of Nrf2 could shorten life of mutant huntingtin

A long-standing question for Huntington’s disease (HD) researchers is why certain nerve cells die, while others appear to be relatively spared by the mutation in the huntingtin gene. It is especially puzzling because in HD patients, the mutant huntingtin gene can be found in every cell in the body, yet it appears to preferentially strike neurons in a region of the brain called the striatum.

In a study supported by HDSA and published July 21st in the journal Nature Chemical Biology, Andrey Tsvetkov, Steven Finkbeiner and their colleagues from the Gladstone Institute of Neurological Disease and the University of California, San Francisco (UCSF) showed that differences in the rate of proteostasis may be the clue they needed in understanding why striatal neurons die first in HD.  Proteostasis is a biological system the body uses to maintain essential protein levels and perform quality control of the various proteins expressed in a given cell.

To study proteostasis in a cell, the UCSF researchers developed a new technique called optical pulse labeling. It allows them to track the lifespan of the normal and mutant huntingtin proteins that they expressed in individual rat brain neurons derived from the cortex, striatum and cerebellum.  They can visualize the huntingtin proteins, because they were made to also express a fluorescent marker that can be seen under a microscope.  The fluorescent signal emitted from each huntingtin protein allows them to measure the time the proteins exist within each type of cell.

They found that the lifetime of the huntingtin protein predicted neuronal survival.  In other words,   shorter lifetimes of mutant huntingtin were associated with longer neuron survival. The cellular environment of the neuron (striatal, cortical or cerebellar) was also found to play an important role in the stability of huntingtin. Striatal neurons cleared mutant huntingtin more slowly than cortical or cerebellar neurons suggesting that the efficiency of the proteostasis system in these different cell populations differs in their ability to clear huntingtin.   This observation could help explain the increased susceptibility of the striatum in HD. It raises the possibility that if we stimulated the proteostasis system with experimental therapies it could help shorten huntingtin lifetime and improve neuronal well-being.

To test this idea, Tsvetkov et al over-expressed Nrf2, a transcription factor known to regulate protein processing and the antioxidant response pathway. When Nrf2 was expressed in striatal neurons expressing a mutant huntingtin with 46 polyglutamines, the mean lifetime of huntingtin was shortened, and the neuron lived longer.

Drugs that are reported to activate the Nrf2 protein are known.  One of them, dimethylfumarate (Tecfidera) was recently approved by the FDA for use in multiple sclerosis.  It remains to be seen it dimethylfumarate or other Nrf2 stimulating compounds will have a beneficial effect in HD.

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References:  Tsvetkov AS et al. Proteostasis of polyglutamine varies among neurons and predicts neurodegeneration. Nature Chemical Biology, July 21, 2013.