title: Spinal muscular atrophy astrocytes exhibit abnormal calcium regulation and reduced growth factor production.
abstract: Spinal muscular atrophy (SMA) is a genetic disorder caused by the deletion of the survival motor neuron 1 (SMN1) gene that leads to loss of motor neurons in the spinal cord. Although motor neurons are selectively lost during SMA pathology, selective replacement of SMN in motor neurons does not lead to full rescue in mouse models. Due to the ubiquitous expression of SMN, it is likely that other cell types besides motor neurons are affected by its disruption and therefore may contribute to disease pathology. Here we show that astrocytes in SMAΔ7 mouse spinal cord and from SMA-induced pluripotent stem cells exhibit morphological and cellular changes indicative of activation before overt motor neuron loss. Furthermore, our in vitro studies show mis-regulation of basal calcium and decreased response to adenosine triphosphate stimulation indicating abnormal astrocyte function. Together, for the first time, these data show early disruptions in astrocytes that may contribute to SMA disease pathology.
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin. 8701 Watertown Plank Rd, Milwaukee, WI 53226.
authors.forename: Jered V
authors.initials: JV
authors.lastname: McGivern
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin. 8701 Watertown Plank Rd, Milwaukee, WI 53226.
authors.forename: Teresa N
authors.initials: TN
authors.lastname: Patitucci
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin. 8701 Watertown Plank Rd, Milwaukee, WI 53226.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Nord
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin. 8701 Watertown Plank Rd, Milwaukee, WI 53226.
authors.forename: Marie-Elizabeth A
authors.initials: MA
authors.lastname: Barabas
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin. 8701 Watertown Plank Rd, Milwaukee, WI 53226.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Stucky
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin. 8701 Watertown Plank Rd, Milwaukee, WI 53226.
authors.forename: Allison D
authors.initials: AD
authors.lastname: Ebert
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000367:Age Factors; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002461:Cell Line, Transformed; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D064231:Nestin / Q000378:metabolism; D000587:Oxidoreductases Acting on CH-NH Group Donors; D039904:Pluripotent Stem Cells / Q000378:metabolism; D058473:Receptors, Purinergic P2Y2 / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000378:metabolism; D000099295:Formyltetrahydrofolate Dehydrogenase
chemical_list: D000255:Adenosine Triphosphate; D000444:Aldehyde Dehydrogenase; D002118:Calcium; D002795:Choline O-Acetyltransferase; D051100:Glial Cell Line-Derived Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D064231:Nestin; D000587:Oxidoreductases Acting on CH-NH Group Donors; D058473:Receptors, Purinergic P2Y2; D009418:S100 Proteins; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D000099295:Formyltetrahydrofolate Dehydrogenase; C526477:SMN2 protein, human; C526472:Smn1 protein, mouse
keywords: astrocyte activation; cell autonomous; motor neurons; stem cells