X‐linked spinal muscular atrophy in mice caused by autonomous loss of ATP7A in the motor neuron

Abstract

ATP7A is a copper transporting P-type ATPase that is essential for cellular copper homeostasis. Loss-of-function mutations in the ATP7A gene result in Menkes disease, a fatal neurodegenerative disorder resulting in seizures, hypotonia, and failure to thrive due to systemic copper deficiency. Most recently, rare missense mutations in ATP7A that do not impact systemic copper homeostasis have been shown to cause X-linked Spinal Muscular Atrophy type 3 (SMAX3), a distal hereditary motor neuropathy. An understanding of the mechanistic and pathophysiological basis of SMAX3 is currently lacking, in part because the disease-causing mutations have been shown to confer both loss- and gain-of-function properties to ATP7A, and because there is currently no animal model of the disease. In this study, the Atp7a gene was specifically deleted in the motor neurons of mice resulting in a degenerative phenotype consistent with the clinical features in affected patients with SMAX3, including the progressive deterioration of gait, age-dependent muscle atrophy, denervation of neuromuscular junctions, and a loss of motor neuron cell bodies. Taken together these data reveal autonomous requirements for ATP7A that reveal essential roles for copper in the maintenance and function of the motor neuron, and suggest that SMAX3 is caused by a loss of ATP7A function that specifically impacts in the spinal motor neuron.

Characterizing the molecular phenotype of an Atp7aT985Iconditional knock in mouse model for X-linked distal hereditary motor neuropathy (dHMNX)

“…Abnormal function of Cu dependent enzymes, including cytochrome c oxidase 41 and superoxide dismutase 1 42 have been associated with Charcot-Marie-Tooth and amyotrophic lateral sclerosis (ALS), respectively. In addition, Atp7a loss of function at the TGN is consistent with outcomes from the Atp7a MN/Y mice in which the degenerative motor neuropathy of the animals is associated with an overall decrease in Cu in the spinal cord 22 . Our ICP-MS data showing a non-significant reduction in the levels of Cu in the sciatic nerve of the Atp7a T985I/Y mice will need further investigation.…”

“…The juvenile onset of distal muscular atrophy in the dHMNX patients harboring the T994I mutation 21 suggests this mutation produces attenuated effects that require years for patients to present with pathological consequences and this would provide a possible rationale for the absence of a global motor phenotype in the Atp7a T985I mice. The previously reported Atp7a MN/Y mouse model, in which Atp7a had been completely knocked out in the motor neurons, only exhibited behavioral abnormalities after 6 months of age 22 . This suggests the possibility of compensatory processes occurring in mice that would mitigate the absence or pathogenic function of mutant Atp7a within the motor neurons.…”

Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SODG93A mice co-expressing the Copper-Chaperone-for-SOD

“…The vulnerability of motor neurons to altered copper homeostasis is highlighted by the discovery that specific mutations in the copper transporter ATP7A occur in progressive X-linked spinal muscular atrophy type 3 (SMAX3) (50). A causal linkage is supported by the targeted knockout in motor neurons of ATP7A in mice, which results in motor neuron degeneration (51). …”

Copper trafficking to the secretory pathway

“…The reason behind this phenomenon is not clear; one possible explanation could be that kidneys are the primary acceptors of small amounts of Cu that exit the intestine through the non-ATP7A related mechanisms. Cu accumulation is also seen in a mouse model of X-linked spinal muscular atrophy, 103 where ATP7A is selectively inactivated in motor neurons. This genetic intervention causes Cu accumulation in neurons without significant changes in Cu levels else-where.…”