TheWld^sMutation Delays Robust Loss of Motor and Sensory Axons in a Genetic Model for Myelin-Related Axonopathy

Abstract

Mice deficient in the peripheral myelin component P0 mimic severe forms of inherited peripheral neuropathies in humans, with defective myelin formation and consequent axonal loss. We cross-bred these mice with the spontaneous mutant C57BL/Wld(s) typically showing protection from Wallerian degeneration because of fusion of the ubiquitination factor E4B (Ube4b) and nicotinamide mononucleotide adenylyltransferase (Nmnat) genes. We found that in the double mutants, the robust myelin-related axonal loss is reduced at 6 weeks and 3 months of age. Moreover, retrograde labeling from plantar nerves revealed an increased survival of motor axons. These motor axons appeared functionally active because both the amplitude of compound muscle action potentials and muscle strength were less reduced in the double mutants. At 6 months of age, reduction of axonal loss was no longer detectable in the double mutants when compared with littermates carrying the P0 null mutation only, although the Wld(s) gene was not reduced in its expression at this age. We conclude that myelin-related axonal loss is a process having some features in common with Wallerian degeneration. Introducing the Wld(s) gene would be a promising approach to delaying detrimental axonal loss in myelin disorders.

NAD+ and axon degeneration revisited: Nmnat1 cannot substitute for WldS to delay Wallerian degeneration

“…The existence of Wld S is an extraordinary experiment of nature that will no doubt provide valuable clues to the causes of axonal degeneration in human diseases. Wld S is truly neuroprotective and has been shown to modify disease course in animal models of toxic neuropathy, 10 CharcotMarie-Tooth neuropathy, 8 motor neuronopathy, 2 amyotrophic lateral sclerosis 32 and Parkinson's disease. 11 Defining the precise mechanism of axonal protection in Wld S mice is thus an important step for developing novel therapeutics for peripheral neuropathies and other disorders of axonal degeneration.…”

“…Two antibodies raised against the Wld S protein, 183 and Wld-18, were used to demonstrate expression of Ube4b/Nmnat1 and W258A, as described previously. 8,14 Expression of Nmnat1 was demonstrated with a polyclonal antibody to Nmnat1 (D20 from Santa Cruz Biotech, 1 : 100 concentration).…”

“…[1][2][3][4][5] Wallerian degeneration distal to an axonal injury is an important and relevant experimental model of axon degeneration in disease. A dominant mutation that delays Wallerian degeneration 10-fold in slow Wallerian degeneration (Wld S ) mice and rats, 6,7 also delays axon degeneration in genetic and toxic 'dying-back' disorders, 2,[8][9][10][11] indicating similarities in the underlying mechanisms. Thus, understanding the Wallerian degeneration mechanism should help to understand how axons degenerate in disease.…”

“…15,16 Wld S encodes a fusion protein containing 70 N-terminal amino acids of ubiquitination factor Ube4b, full-length nicotinamide adenine dinucleotide (NAD þ )-synthesising enzyme nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1), and a unique 18-amino-acid joining sequence. 15 Surprisingly, Wld S is abundant in neuronal nuclei 8,11,15,18 and so far undetectable in axons in vivo. However, it does enter neurites in virally transduced primary cultures.…”

Mouse Forward Genetics in the Study of the Peripheral Nervous System and Human Peripheral Neuropathy

“…Therefore, the novel function exhibited by the Wld S protein appears to be intrinsic to the whole chimera [47]. While the molecular mechanism of Wld S protection remains enigmatic, crossing the Wld S mutant with other models of neuropathy, such as progressive motor neuronopathy [48], gracile axonal dystrophy [49], and the myelin protein zero (Mpz) knockout [50], has helped probe the role of axon degeneration in these disorders.…”