Axonal degeneration as a therapeutic target for ALS
One of the neuron’s most impressive morphological features is their long axonal projections, which are the basis of the complex, precise, and fast-firing neuronal network. To protect these fragile structures, neurons possess mechanisms to actively regulate axonal survival and degeneration, that are independent of the programmed cell death of the cell body. Axonal damage has been observed in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), showing early-stage axonal degeneration. This degeneration has been proven to be sufficient to cause symptoms, even though the cell bodies remain intact. These data indicate that axonal degeneration should be considered as a critical part in the early stages of ALS. Much is known about the regeneration processes that occur in response to acute mechanical injury or axotomy. However, little is known about the genetic pathways regulating repair and regeneration in the context of age-dependent axon degeneration observed in ALS.
We hypothesize that stimulation of pro-axon regeneration genetic pathways may inhibit age-dependent axon degeneration observed in ALS. We found that genetic and pharmaceutical activation of several axonal regeneration pathways reduce motor deficits and axon degeneration in our C. elegans ALS models. We will validate key genes and drugs in zebrafish and iPSC models of ALS. Identifying pathways and genes that regulate axonal dynamics in ALS may lead to the development of new therapeutic strategies which can protect both the cell body and the axon, thus potentially delaying or preventing disease onset.
Alex Parker , Centre hospitalier de l’Université de Montréal
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