Type

Journal Article

Authors

Jochen H M Prehn
Philippe Marin
Caoimhín G Concannon
Dairin Kieran
Bridget Breen
Karen Coughlan
Heiko Düssmann
Isabela M Aparicio
Matthew A King
Alexandra Skorupa

Subjects

Biochemistry

Topics
transfection rna cleavage cells cultured mice endocytosis culture media conditioned cells real time polymerase chain reaction ribonuclease pancreatic ribonuclease pancreatic cultured female protein binding metabolism syndecan 4 blotting paracrine communication physics clathrin blotting western culture media neuroprotective agents cell survival male mice inbred c57bl conditioned inbred c57bl physiology motor neurons immunohistochemistry western angiogenin astrocytes animals

Motoneurons secrete angiogenin to induce RNA cleavage in astroglia. (2012)

Abstract 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.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed
Ireland -> Royal College of Surgeons in Ireland -> Physiology and Medical Physics Articles
Ireland -> Royal College of Surgeons in Ireland -> Department of Physiology and Medical Physics

Full list of authors on original publication

Jochen H M Prehn, Philippe Marin, Caoimhín G Concannon, Dairin Kieran, Bridget Breen, Karen Coughlan, Heiko Düssmann, Isabela M Aparicio, Matthew A King, Alexandra Skorupa

Experts in our system

1
Jochen H M Prehn
Royal College of Surgeons in Ireland
Total Publications: 206
 
2
Caoimhín G Concannon
Royal College of Surgeons in Ireland
Total Publications: 46
 
3
Karen S Coughlan
Royal College of Surgeons in Ireland
Total Publications: 10
 
4
Heiko Düssmann
Royal College of Surgeons in Ireland
Total Publications: 45