Motor neuron pathology and behavioral alterations at late stages in a SMA mouse model.
Spinal muscular atrophy (SMA) is a neurogenetic autosomal recessive disorder characterized by degeneration of lower motor neurons. The validation of appropriate animal models is key in fostering SMA research. Recent studies set up an animal model showing long survival and slow disease progression. This model is knocked out for mouse SMN (Smn(-/-)) gene and carries a human mutation of the SMN1 gene (SMN1A2G), along with human SMN2 gene. In the present study we used this knock out double transgenic mouse model (SMN2(+/+); Smn(-/-); SMN1A2G(+/-)) to characterize the spinal cord pathology along with motor deficit at prolonged survival times. In particular, motor neuron loss was established stereologically (44.77%) after motor deficit reached a steady state. At this stage, spared motor neurons showed significant cell body enlargement. Moreover, similar to what was described in patients affected by SMA we found neuronal heterotopy (almost 4% of total motor neurons) in the anterior white matter. The delayed disease progression was likely to maintain fair motor activity despite a dramatic loss of large motor neurons. This provides a wonderful tool to probe novel drugs finely tuning the survival of motor neurons. In fact, small therapeutic effects protracted over considerable time intervals (even more than a year) are expected to be magnified.
Department of Human Morphology and Applied Biology, University of Pisa, via Roma, 55, 56126, Pisa, Italy. ffulceri@libero.it
Federica
F
Fulceri
Alessia
A
Bartalucci
Silvio
S
Paparelli
Livia
L
Pasquali
Francesca
F
Biagioni
Michela
M
Ferrucci
Riccardo
R
Ruffoli
Francesco
F
Fornai
D000818:Animals; D048429:Cell Size; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity; D009046:Motor Neurons / Q000473:pathology*; D018908:Muscle Weakness; D009134:Muscular Atrophy, Spinal / Q000473:pathology* / Q000503:physiopathology; D009410:Nerve Degeneration; D012018:Reflex; D045442:Rotarod Performance Test; D013116:Spinal Cord / Q000473:pathology*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics
C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein