21 March 2008. A paper out March 16 in Nature Neuroscience from Berislav Zlokovic and colleagues at the University of Rochester in New York finds that mice expressing SOD1 mutations associated with inherited forms of amyotrophic lateral sclerosis (ALS) show vascular defects early in life, before motor neurons begin to degenerate. First author Zhihui Zhong and coworkers present evidence for a leaky blood-spinal cord barrier associated with microhemorrhages, neuroinflammation, reduced capillary density, and lowered blood flow. The researchers conclude that compromised circulation is an early event that could contribute to degeneration of motor neurons in these ALS models.
Previous work has shown breaches in the blood-brain barrier in symptomatic SOD1 mice with early or advanced disease (Garbuzova-Davis et al., 2007). In the new study, the effects show up presymptomatically, and get progressively worse with time. The appearance of vascular defects as early as two months of age precedes the onset of inflammation, and that then leads to further damage to the blood-brain barrier (BBB) as observed in people with ALS (Graves et al., 2004).
“Our study demonstrates that changes to the vasculature probably make an important contribution to the degeneration of large motor neurons in familial models of ALS,” the researchers conclude. The vascular changes, they showed, appeared to result from decreases in the expression of the tight junction proteins ZO-1, occludin and claudin-5 in endothelial cells that make up the BBB. “All of this evidence supports the idea that mutant-mediated damage to the vasculature contributes to initiating non-cell autonomous killing of motor neurons in inherited ALS,” they write.—Pat McCaffrey.
Zhong Z, Deane R, Ali Z, Parisi M, Shapovalov Y, O'Banion MK, Stojanovic K, Sagare A, Boillee S, Cleveland DW, Zlokovic BV. ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nat Neurosci. 2008 Mar 16; [Epub ahead of print] Abstract