Angiogenin induces modifications in the astrocyte secretome: relevance to amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting lower and upper motoneurons. Recent studies have shown that both motor neurons and non-neuronal neighbouring cells such as astrocytes and microglia contribute to disease pathology. Loss-of-function mutations in the angiogenin (ANG) gene have been identified in ALS patients. Angiogenin is enriched in motor neurons and exerts neuroprotective effects in vitro and in vivo. We have recently shown that motoneurons secrete angiogenin, and that secreted angiogenin is exclusively taken up by astrocytes, suggesting a paracrine mechanism of neuroprotection. To gain insights into astrocyte effectors of angiogenin-induced neuroprotection, we examined alterations in the astrocyte secretome induced by angiogenin treatment using quantitative proteomics based on Stable Isotope Labelling by Amino Acids in Cell Culture (SILAC). We identified 2128 proteins in conditioned media from primary cultured mouse astrocytes, including 1247 putative secreted proteins. Of these, 60 proteins showed significant regulation of secretion in response to angiogenin stimulation. Regulated proteins include chemokines and cytokines, proteases and protease inhibitors as well as proteins involved in reorganising the extracellular matrix. In conclusion, this proteomic analysis increases our knowledge of the astrocyte secretome and reveals potential molecular substrates underlying the paracrine, neuroprotective effects of angiogenin.


CONCLUSIONS
This study provides the most extensive list of astrocyte-secreted proteins available and reveals novel potential molecular substrates of astrocyte-neuron communication. It also identifies a set of astrocyte-derived proteins that might slow down ALS disease progression. It should be relevant to a large readership of neuroscientists and clinicians, in particular those with an interest in the physiological and pathological roles of astrocytes and in the molecular and cellular mechanisms underlying neurodegenerative disorders.
Institut de Génomique Fonctionnelle, CNRS UMR 5203, F-34094 Montpellier, France; INSERM U661, F-34094 Montpellier, France; Université Montpellier I, F-34094 Montpellier, France; Université Montpellier II, F-34094 Montpellier, France; Royal College of Surgeons in Ireland, Dept. of Physiology and Medical Physics, Dublin 2, Ireland.
Alexandra
A
Skorupa
Serge
S
Urbach
Oana
O
Vigy
Matthew A
MA
King
Séverine
S
Chaumont-Dubel
Jochen H M
JH
Prehn
Philippe
P
Marin
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D002450:Cell Communication; D002470:Cell Survival; D017077:Culture Media, Conditioned / Q000737:chemistry; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D020543:Proteome; D040901:Proteomics; D012259:Ribonuclease, Pancreatic / Q000378:metabolism*
D017077:Culture Media, Conditioned; D020543:Proteome; C046366:angiogenin; D012259:Ribonuclease, Pancreatic
Amyotrophic lateral sclerosis; Angiogenin; Astrocyte; SILAC; Secretome