TY - JOUR
T1 - Spinal muscular atrophy pathogenic mutations impair the axonogenic properties of axonal-survival of motor neuron
AU - Locatelli, Denise
AU - D'Errico, Paolo
AU - Capra, Silvia
AU - Finardi, Adele
AU - Colciaghi, Francesca
AU - Setola, Veronica
AU - Terao, Mineko
AU - Garattini, Enrico
AU - Battaglia, Giorgio
PY - 2012/5
Y1 - 2012/5
N2 - 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.
AB - 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.
KW - axon growth
KW - axon swellings
KW - cytoskeletal abnormalities
KW - motor neuron
KW - spinal muscular atrophy
KW - Tudor domain
UR - http://www.scopus.com/inward/record.url?scp=84859605621&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84859605621&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2012.07689.x
DO - 10.1111/j.1471-4159.2012.07689.x
M3 - Article
C2 - 22324632
AN - SCOPUS:84859605621
VL - 121
SP - 465
EP - 474
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 3
ER -