ALS-Causing Mutations Impair TDP43 Transport in Nerve Cells

by Amy Madsen on Wed, 2014-03-12 14:28

Findings show TDP43 protein transports RNA molecules in motor neurons; impairment of the function may help drive the amyotrophic lateral sclerosis disease process

Normally, TDP43 helps transport vital cargo up and down the axon that extends from the cell body of each motor neuron, and chemical signals pass from nerve cells to muscle fibers via the axon terminal. When TDP43 is abnormal, this transport process is impaired.
Article Highlights:
  • TDP43 protein appears to play a role in the transport of RNA molecules — a function that is impaired in the presence of ALS-causing TDP43 mutations.
  • Loss of TDP43's transport function is one of several possible mechanisms that may contribute to the ALS disease process.
  • Therapeutic strategies aimed at preserving TDP43’s transport role may be beneficial in ALS and related neurodegenerative diseases.

TDP43 protein is involved in the transport of vital cargo within motor neurons, the muscle-controlling nerve cells that are lost in amyotrophic lateral sclerosis (ALS), a multinational research team reports. Further, disruption of the function results from ALS-causing mutations in the gene for the TDP43 protein and may contribute to the ALS disease process.

The researchers, led by J. Paul Taylor at St. Jude Children’s Research Hospital in Memphis, detected impairments to the transport function caused by TDP43 mutations in fruit fly and mouse models of ALS, as well as in motor neurons derived from stem cells taken from ALS patients. They showed how impairments in the function might contribute to the nerve cell loss that is a hallmark of the disease.

The findings, which were reported online Feb. 5, 2014, in Neuron, suggest that therapeutic strategies aimed at preserving TDP43’s transport role may be beneficial in ALS and related neurodegenerative diseases.

TDP43 a known contributor to ALS

TDP43 protein is a major component of the clumps called inclusions that are found in the dying motor neurons in nearly all people with ALS, and mutations in the gene for the TDP43 protein are known to cause both familial and sporadic cases of the disease.

In ALS, TDP43, which normally resides in the cell nucleus, improperly locates in the main compartment of the cell called the cytoplasm, the effect this has on the protein’s normal function has remained unclear.

TDP43 transport moves RNA molecules in nerve cells

In fruit fly research models, Taylor and colleagues found that normal TDP43 protein localized in the cell nucleus as expected, but that it also appeared in the cytoplasm in RNA granules. RNA granules contain RNA molecules and RNA-binding proteins that participate in key RNA-related processes.

The researchers noted that RNA granules were distributed throughout the axon, the long fiber that extends from the nerve cell body and through which signals are passed to muscles or other neurons. Importantly, these TDP43-containing granules were found even at the distal end of the neuron (the end farthest away from the cell body) and at the neuromuscular junction (the place where communication takes place between muscle and nerve).

Using an imaging technique, the researchers were able to visualize TDP43-containing granules moving up and down axons. The granules moved in both directions, often for long distances, paused for a bit, and then continued their journey.

ALS-causing TDP43 mutations impaired axonal transport

In fruit fly models containing either of two different ALS-associated mutations, the TDP43 transport process involved in transporting RNA was impaired, preventing TDP43 from traveling to the end of the axon.

In imaging studies, compared to normal TDP43, the ALS-linked mutant TDP43-containing granules were transported less efficiently; their movements were interrupted with more pauses. The impaired process resulted in a diminished ability for TDP43 granules to reach the distal end of axons and the neuromuscular junction.

Next, in studies conducted in mouse nerve cells, the team confirmed that TDP43 joined with RNA transport granules and trafficked down the axons. The process was less efficient, with more pauses and direction reversals, in models containing TDP43 mutations.

Finally, the team validated its findings in human patient-derived cells. Researchers obtained induced pluripotent stem (iPS) cells from ALS patients harboring three different TDP43 mutations, along with control cells from healthy individuals. They developed these cells into motor neurons and compared the efficiency of RNA granule transport and found, just as in the fly and mouse experiments, that neurons harboring TDP43 mutations exhibited impairments in the RNA transport process.

The results indicate an association between TDP43 mutations and impairment to the RNA transport process in motor neurons, and suggest that one mechanism by which TDP43 mutations can contribute to the ALS disease process is through the loss of one of its normal functions.

Learn more about TDP43 and transport in ALS

To read more about TDP43 and transport problems in ALS, see:

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