ALS-causative Mutations Directly Affect Sensory Nerves’ Growth and Stress Response, Preclinical Study Shows

ALS-causative Mutations Directly Affect Sensory Nerves’ Growth and Stress Response, Preclinical Study Shows

Sensory nerves carrying mutations in the TDP-43 or SOD1 genes — associated with the development of amyotrophic lateral sclerosis (ALS) — show impaired growth and stress responses, according to a preclinical study.

The study, “The ALS-inducing factors, TDP43A315T and SOD1G93A, directly affect and sensitize sensory neurons to stress,” was published in the journal Scientific Reports.

The hallmark of ALS is the death of motor nerve cells, which control voluntary muscles. But recent evidence has highlighted that ALS also leads to dysfunction and degeneration of sensory nerve cells.

Sensory nerves send information from the peripheral tissues (such as skeletal muscles) to the central nervous system (brain and spinal cord) to regulate motor function.

Sensory nerves’ dysfunction has been associated with cellular changes similar to those found in motor nerves affected by ALS and to occur before the onset of ALS-related motor function deficits.

While mutations in the SOD1TDP-43, FUS, and C9ORF72 genes have been shown to cause familial ALS, so far, only SOD1 mutations have been shown to affect sensory nerves by degenerating their axons (the fiber-like structures responsible for conducting messages between nerve cells).

The transport of molecules within the nerve cells’ axons is important for axon growth or regeneration and nerve cell communication, and both SOD1 and TDP43 mutations have been associated with impaired axonal transport.

Researchers have now evaluated whether TDP43 mutations also directly affected sensory nerve cells and reanalyzed the effects of SOD1 mutations in these cells.

The team collected and analyzed sensory nerve cells — both as an intact cluster of nerve cells or as isolated cells grown in the lab — from ALS mouse models with TDP43 or SOD1 mutations.

The results showed that sensory nerve cells carrying either TDP43 or SOD1 mutations had significantly shorter and less complex axons, which also growed at a slower rate, than sensory nerves from healthy mice.

Also, cells with either ALS-causative mutation were more sensitive to cellular stress induced by vincristine — a compound that causes progressive degeneration of axons at low doses — than healthy sensory nerves.

Interestingly, all these negative effects were significantly stronger in sensory nerves with TDP43 mutations than in those with SOD1 mutations, suggesting that TDP43 has a major effect in the molecular and cellular events involved in regeneration and growth of sensory nerves.

The team also found that the levels of two molecules involved in stress responses — ATF3 and PERK — were altered in sensory nerves with mutations in TDP43 or SOD1 genes, compared with those in healthy cells.

Additionally, these levels were significantly lower in TDP43-mutated sensory nerves cultured in the lab, compared with healthy and SOD1-mutated nerves, which may explain the stronger impairment observed for TDP43-mutated sensory nerves.

The researchers noted that lower levels of ATF3 and PERK may contribute to the accumulation of toxic features caused by TDP43 mutations in sensory nerves, but additional studies are required to confirm these associations and the differences between TDP43– and SOD1-mutated sensory nerves.

These findings suggest that TDP43 mutations, in addition to SOD1 mutations, directly affect sensory nerve cells in ALS, and that similar molecular mechanisms affecting axons may become dysfunctional in both sensory and motor nerve cells in ALS.

“Thus, molecular analysis of these two [nerve cell types] should be undertaken in future experiments to uncover mechanisms that function to maintain and repair their respective [axons and] nerve endings,” which could be “therapeutic targets for preventing, slowing and even reversing” ALS-development, the researchers wrote.

One comment

  1. Dave Reckonin says:

    “These findings suggest that TDP43 mutations, in addition to SOD1 mutations, directly affect sensory nerve cells in ALS, ..”

    This is very old news, surely ?

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