RT Journal Article
SR Electronic
T1 Motoneurons Secrete Angiogenin to Induce RNA Cleavage in Astroglia
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 5024
OP 5038
DO 10.1523/JNEUROSCI.6366-11.2012
VO 32
IS 15
A1 Alexandra Skorupa
A1 Matthew A. King
A1 Isabela M. Aparicio
A1 Heiko Dussmann
A1 Karen Coughlan
A1 Bridget Breen
A1 Dairin Kieran
A1 Caoimhin G. Concannon
A1 Philippe Marin
A1 Jochen H. M. Prehn
YR 2012
UL http://www.jneurosci.org/content/32/15/5024.abstract
AB Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder affecting motoneurons. Mutations in angiogenin, encoding a member of the pancreatic RNase A superfamily, segregate with ALS. We previously demonstrated that angiogenin administration shows promise as a neuroprotective therapeutic in studies using transgenic ALS mice and primary motoneuron cultures. Its mechanism of action and target cells in the spinal cord, however, are largely unknown. Using mixed motoneuron cultures, motoneuron-like NSC34 cells, and primary astroglia cultures as model systems, we here demonstrate that angiogenin is a neuronally secreted factor that is endocytosed by astroglia and mediates neuroprotection in paracrine. We show that wild-type angiogenin acts unidirectionally to induce RNA cleavage in astroglia, while the ALS-associated K40I mutant is also secreted and endocytosed, but fails to induce RNA cleavage. Angiogenin uptake into astroglia requires heparan sulfate proteoglycans, and engages clathrin-mediated endocytosis. We show that this uptake mechanism exists for mouse and human angiogenin, and delivers a functional RNase output. Moreover, we identify syndecan 4 as the angiogenin receptor mediating the selective uptake of angiogenin into astroglia. Our data provide new insights into the paracrine activities of angiogenin in the nervous system, and further highlight the critical role of non-neuronal cells in the pathogenesis of ALS.