Davenport_2016_Neurodegener.Dis_16_260

BACKGROUND: Mast syndrome, an autosomal recessive, progressive form of hereditary spastic paraplegia, is associated with mutations in SPG21 loci that encode maspardin protein. Although SPG21-/- mice exhibit lower limb dysfunction, the role of maspardin loss in mast syndrome is unclear. OBJECTIVE: To test the hypothesis that loss of maspardin attenuates the growth and maturation of cortical neurons in SPG21-/- mice. METHODS AND
RESULTS: In a randomized experimental design SPG21-/- mice demonstrated significantly less agility and coordination compared to wild-type mice in beam walk, ledge, and hind limb clasp tests for assessing neuronal dysfunction (p <= 0.05). The SPG21-/- mice exhibited symptoms of mast syndrome at 6 months which worsened in 12-month-old cohort, suggesting progressive dysfunction of motor neurons. Ex vivo, wild-type cortical neurons formed synapses, ganglia and aggregates at 96 h, whereas SPG21-/- neurons exhibited attenuated growth with markedly less axonal branches. Additionally, epidermal growth factor markedly promoted the growth and maturation of SPG21+/+ cortical neurons but not SPG21-/- neurons. Consequently, quantitative RT-PCR identified a significant reduction in the expression of a subset of EGF-EGFR signaling targets.
CONCLUSIONS: Our current study uncovered a direct role for maspardin in normal and EGF-induced growth and maturation of primary cortical neurons. The loss of maspardin resulted in attenuated growth, axonal branching, and attenuation of EGF signaling. Reinstating the functions of maspardin may reverse hind limb impairment associated with neuronal dysfunction in mast syndrome patients.