Motor neurons aren’t the only site for restoring locomotive function

TBPH mutant larvae show defective motor behavior, which can be rescued by 654 cacophony expression in selected neurons.

TBPH mutant larvae show defective motor behavior, which can be rescued by 654 cacophony expression in selected neurons.

Amyotrophic lateral sclerosis is the most common adult onset motor neuron disease for which there is no cure or treatment that significantly extends life. ALS causes the death of neurons that control voluntary muscles and is characterized by gradually worsening weakness, loss of motor function and, when the individual can no longer breathe, death. The only FDA-approved drug used to treat ALS prolongs on average the lifetime of a patient by two to three months.

A feature in neurodegenerative diseases, including about 90 percent of patients with ALS, is a mutation in the transactivating responsive sequence DNA-binding protein (TDP-43). Neurons are known to be sensitive to TDP-43 expression levels, but the specific defects caused by TDP-43 loss of function have not been described in detail.

Now, in a paper published in the Journal of Neuroscience, a team led by David Morton, Ph.D., has demonstrated that function can be restored by increased expression of a single gene in two central neurons. Conducted in the lab of Morton, professor of integrative biosciences and associate dean of research in the School of Dentistry, the research expanded on Morton’s 2013 discovery that expression of a voltage gated calcium channel restored the loss of motor function in a fruit fly model of ALS.

The team hypothesized that the mechanisms by which TDP-43 expression restores motor function would take place in motor neurons. Kayly Lembke, lead author and graduate student in the Department of Physiology and Pharmacology, found that, in addition to motor neurons, expression of a voltage gated calcium channel in two central neurons in the brain are able to restore motor defects.

The finding that such a small number of neurons—two—can restore motor function is significant. TDP-43 regulates a large number of other genes and, if restoration required a significant number of processes, it would be extremely challenging to target any one of the processes. The discovery that expressing this channel can restore function opens the future possibility of therapeutic strategies that target this channel. This possibility, however, will require substantially more work.

The next step is developing a more targeted model.

 

This study was supported by grants from NINDS (NS071186) and the ALS Association. The OHSU Sequencing and Bioinformatics Cores provided analysis and sequencing for the study.

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Casey has been writing about research about OHSU since September 2016.

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