Zebrafish embryos with muscle decay and a vasculature in disarray suggest that mutations in TDP-43 contribute to amyotrophic lateral sclerosis and frontotemporal dementia by messing with the protein’s normal function. Bettina Schmid and Christian Haass of the German Center of Neurodegenerative Diseases report in this week’s Proceedings of the National Academy of Sciences online that knocking out the zebrafish orthologues of TDP-43 damages organ systems, rendering the embryos not viable. “Our findings not only reveal an unexpected requirement of TDP-43 for muscle maintenance, blood flow, blood vessel formation, and motor neuron axon outgrowth, but may also provide fresh evidence for a loss-of-function disease mechanism in TDP-43 proteinopathies,” the authors conclude.

Alzforum previously reported Schmid and Haass’ meeting presentations, in which they reported that they only achieved a mutant phenotype when they eliminated both fish versions of the gene, TARDBP and “TARDBP-like.” Double-mutant embryos survive for just a week (see ARF related news story; ARF news story). Human TDP-43 rescues the TARDBP-deficient fish, but Schmid and Haass now add that an ALS-linked mutation, glycine-348-cysteine, saves some knockout embryos. This indicates that while a total loss of TARDBP is indeed lethal, a mild mutation can support life for a short time. “We therefore hypothesize that a subtle loss of function … leads over time to ALS and FTLD-TDP pathology,” the authors suggest.

In the paper, the team added an analysis of the proteome created by TARDBP loss. Thirteen proteins were upregulated and 28 downregulated in the double knockouts. Most of the latter were muscle based, fitting with that phenotype. The top upregulated hit was the muscle protein filamin C, with doubled levels in the knockouts. Human filamin C was upregulated in brains from people with FTLD due to TDP-43 proteinopathy, but not Alzheimer’s or neurologically healthy samples.

Filamin C crosslinks actin in multiple types of muscle, including those surrounding blood vessels in the brain. The authors hypothesize that in cases of TDP-43 proteinopathy, an excess of filamin C diminishes blood flow in the brain, and results in the leaky blood-brain barrier and blood-spinal cord barrier observed in people with ALS (Winkler et al., 2012; Ishikawa et al., 2007).—Amber Dance.

Reference:
Schmid B, Hruscha A, Hogl S, Banzhaf-Strathmann J, Strecker K, van der Zee J, Teucke M, Eimer S, Hegermann J, Kittelmann M, Kremmer E, Cruts M, Solchenberger B, Hasenkamp L, van Bebber F, Van Broeckhoven C, Edbauer D, Lichtenthaler SF, Haass C. Loss of ALS-associated TDP-43 in zebrafish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth. Proc Natl Acad Sci U S A. 2013 Mar 1. Abstract

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

  1. A recent paper in Human Molecular Genetics also observed that TARDBPl compensates for the loss of TARDBP.

    References:

    . Tardbpl splicing rescues motor neuron and axonal development in a mutant tardbp zebrafish. Hum Mol Genet. 2013 Jun 15;22(12):2376-86. PubMed.

References

News Citations

  1. Honolulu: TDP-43 Gets a Place in the Sun
  2. TDP-43 Controls Blood Vessels in Fish, Is Phosphorylated in Worms

Paper Citations

  1. . Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathol. 2012 Sep 1; PubMed.
  2. . Constant blood flow reduction in premotor frontal lobe regions in ALS with dementia - a SPECT study with 3D-SSP. Acta Neurol Scand. 2007 Nov;116(5):340-4. PubMed.
  3. . Loss of ALS-associated TDP-43 in zebrafish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth. Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):4986-91. PubMed.

Further Reading

Papers

  1. . Loss of ALS-associated TDP-43 in zebrafish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth. Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):4986-91. PubMed.
  2. . Methylene blue protects against TDP-43 and FUS neuronal toxicity in C. elegans and D. rerio. PLoS One. 2012;7(7):e42117. PubMed.
  3. . Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron. 2010 Nov 4;68(3):409-27. PubMed.
  4. . Gray matter perfusion correlates with disease severity in ALS. Neurology. 2010 Mar 9;74(10):821-7. PubMed.
  5. . ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nat Neurosci. 2008 Apr;11(4):420-2. PubMed.
  6. . VEGF at the neurovascular interface: therapeutic implications for motor neuron disease. Biochim Biophys Acta. 2006 Nov-Dec;1762(11-12):1109-21. PubMed.
  7. . Cerebral blood flow and oxygen metabolism in patients with progressive dementia and amyotrophic lateral sclerosis. Neurol Res. 2003 Jun;25(4):351-6. PubMed.

Primary Papers

  1. . Loss of ALS-associated TDP-43 in zebrafish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth. Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):4986-91. PubMed.