Spinal muscular atrophy pathogenic mutations impair the axonogenic properties of axonal-survival of motor neuron.
The axonal survival of motor neuron (a-SMN) protein is a truncated isoform of SMN1, the spinal muscular atrophy (SMA) disease gene. a-SMN is selectively localized in axons and endowed with remarkable axonogenic properties. At present, the role of a-SMN in SMA is unknown. As a first step to verify a link between a-SMN and SMA, we investigated by means of over-expression experiments in neuroblastoma-spinal cord hybrid cell line (NSC34) whether SMA pathogenic mutations located in the N-terminal part of the protein affected a-SMN function. We demonstrated here that either SMN1 missense mutations or small intragenic re-arrangements located in the Tudor domain consistently altered the a-SMN capability of inducing axonal elongation in vitro. Mutated human a-SMN proteins determined in almost all NSC34 motor neurons the growth of short axons with prominent morphologic abnormalities. Our data indicate that the Tudor domain is critical in dictating a-SMN function possibly because it is an association domain for proteins involved in axon growth. They also indicate that Tudor domain mutations are functionally relevant not only for FL-SMN but also for a-SMN, raising the possibility that also a-SMN loss of function may contribute to the pathogenic steps leading to SMA.
Molecular Neuroanatomy and Pathogenesis Unit, Neurological Institute 'C. Besta', Milano, Italy.
Denise
D
Locatelli
Paolo
P
d'Errico
Silvia
S
Capra
Adele
A
Finardi
Francesca
F
Colciaghi
Veronica
V
Setola
Mineko
M
Terao
Enrico
E
Garattini
Giorgio
G
Battaglia
D000595:Amino Acid Sequence; D001369:Axons / Q000502:physiology* / Q000648:ultrastructure; D015153:Blotting, Western; D048429:Cell Size; D002470:Cell Survival; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000473:pathology / Q000648:ultrastructure; D005455:Fluorescent Antibody Technique; D006822:Hybrid Cells; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000502:physiology* / Q000648:ultrastructure; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics / Q000502:physiology*; D020125:Mutation, Missense / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D013347:Subcellular Fractions / Q000473:pathology / Q000648:ultrastructure; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics*; D014162:Transfection
C526471:SMN1 protein, human; D055533:Survival of Motor Neuron 1 Protein