Abstract
Mice overexpressing proteolipid protein (PLP) develop a leukodystrophy-like disease involving cytotoxic, CD8+ T-lymphocytes. Here we show that these cytotoxic T-lymphocytes perturb retrograde axonal transport. Using fluorogold stereotactically injected into the colliculus superior, we found that PLP overexpression in oligodendrocytes led to significantly reduced retrograde axonal transport in retina ganglion cell axons. We also observed an accumulation of mitochondria in the juxtaparanodal axonal swellings, indicative for a disturbed axonal transport. PLP overexpression in the absence of T-lymphocytes rescued retrograde axonal transport defects and abolished axonal swellings. Bone marrow transfer from wildtype mice, but not from perforin- or granzyme B-deficient mutants, into lymphocyte-deficient PLP mutant mice led again to impaired axonal transport and the formation of axonal swellings, which are predominantly located at the juxtaparanodal region. This demonstrates that the adaptive immune system, including cytotoxic T-lymphocytes which release perforin and granzyme B, are necessary to perturb axonal integrity in the PLP-transgenic disease model. Based on our observations, so far not attended molecular and cellular players belonging to the immune system should be considered to understand pathogenesis in inherited myelin disorders with progressive axonal damage.
Highlights
An important consequence of many myelin disorders is the degeneration of axons
We found that in proteolipid protein (PLP) overexpressing mutants, the presence of functional cytotoxic T-cells is mandatory for glia-induced impairment of retrograde axonal transport and that this pathogenic effect is mediated by perforin and granzyme B
To investigate whether axonal transport is impaired in PLP overexpressing (PLP-tg) mice and, eventually, whether the immune system is involved in this potential perturbation, we first analyzed the axonal transport by retrograde labeling of retina ganglion cells (RGCs) after injection of fluorogold into the colliculus superior. 6 days after tracer injection, we counted 22% less labeled RGCs in the PLP-tg mutants compared to wt mice (p,0.05) (Figure 1A, B)
Summary
An important consequence of many myelin disorders is the degeneration of axons. it is well established that myelin and glial perturbation often leads to axon damage, the mechanisms involved are not yet entirely understood. Using mice overexpressing PLP and serving as a model for X-linked spastic paraplegia type-2 [6,7] our laboratory recently identified cytotoxic T-lymphocytes as mediators of primarily gliogenic neural damage [8,9,10,11] It was not investigated whether the low-grade inflammation affected axonal transport. We found that in PLP overexpressing mutants, the presence of functional cytotoxic T-cells is mandatory for glia-induced impairment of retrograde axonal transport and that this pathogenic effect is mediated by perforin and granzyme B. This finding substantially extends our knowledge about the pathomechanisms underlying primarily gliogenic axon perturbation
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