The mechanism by which SOD1 leads to motor neuron death in ALS is of great interest; much controversy has surrounded which are the relevant cell type(s) in which mutant SOD1 exerts its deleterious effects. This is a very interesting study demonstrating early blood-brain barrier (BBB) defects in the SOD1 mutant mouse model of ALS prior to frank neurodegeneration. SOD1 is expressed at very high levels in brain endothelial cells (our unpublished gene profiling data), up to twice the level of other brain cell types, and they may be preferentially vulnerable to injury in SOD1 mutants for this reason. The blood-brain barrier breakdown is also increasingly implicated in Alzheimer disease, though it remains unclear whether such changes occur early in AD or late in AD.

In the present paper the provocative observation is that these changes occur early. This is particularly interesting because of new (e.g., Stevens et al., 2007; Lobsiger et al., 2007) and old work (reviewed in   Read more

The mechanism by which SOD1 leads to motor neuron death in ALS is of great interest; much controversy has surrounded which are the relevant cell type(s) in which mutant SOD1 exerts its deleterious effects. This is a very interesting study demonstrating early blood-brain barrier (BBB) defects in the SOD1 mutant mouse model of ALS prior to frank neurodegeneration. SOD1 is expressed at very high levels in brain endothelial cells (our unpublished gene profiling data), up to twice the level of other brain cell types, and they may be preferentially vulnerable to injury in SOD1 mutants for this reason. The blood-brain barrier breakdown is also increasingly implicated in Alzheimer disease, though it remains unclear whether such changes occur early in AD or late in AD.

In the present paper the provocative observation is that these changes occur early. This is particularly interesting because of new (e.g., Stevens et al., 2007; Lobsiger et al., 2007) and old work (reviewed in McGeer et al., 2005) suggesting complement activation in neurodegenerative disease, including the mouse model of ALS and in human ALS. The blood-brain barrier leakage will thus enable high levels of complement proteins to enter the CNS, and these might contribute ultimately to triggering neuroinflammation. It will be of great interest in future studies to see if endothelial expression of mutant SOD1 and/or blood-brain barrier breakdown is required for motor neuron degeneration to occur, and whether prevention of BBB breakdown can lessen the motor neuron degeneration.

View all comments by Ben Barres

This is a thorough and important work, confirming and extending our original findings of dysfunction and structural damage, vascular leakage and edema, in the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) even in early-symptomatic G93A ALS mice (Garbuzova-Davis et al., 2007). The authors found BSCB damage in presymptomatic mice and in other ALS mouse models expressing different SOD mutations. Importantly, as we already know that inflammatory processes can alter the BBB, damage was noted in mice prior to the onset of inflammation. This also may have implications for other neurodegenerative diseases such as Alzheimer’s and Parkinson’s, where BBB damage has already been identified in patients. This finding, and our previous findings, may lead to revised pharmaceutical treatments for ALS, some of which assume a functional, intact BBB/BSCB. However, the article leaves open the questions of which disease mechanisms are affecting the BBB/BSCB and, our current focus, how the BBB/BSCB may be repaired.

View all comments by Svitlana Garbuzova-Davis

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

References:
Hewamadduma CA, Grierson AJ, Ma TP, Pan L, Moens CB, Ingham PW, Ramesh T, Shaw PJ. Tardbpl splicing rescues motor neuron and axonal development in a mutant tardbp zebrafish. Hum Mol Genet. 2013 Mar 3. Abstract

View all comments by Tennore Ramesh