A New Mouse Mutant with Progressive Motor Neuronopathy

Abstract

A new autosomal-recessive mouse mutant with progressive motor neuronopathy (pmn) is described. Homozygotes develop paralysis of the hindlimbs during the third week of life. Soon thereafter the forelimbs also become weak, and all mice die six to seven weeks after birth. Heterozygotes are normal. Skeletal muscles show neurogenic atrophy without histological signs of reinnervation. Axonal degeneration apparently starts at the endplates and is prominent in the sciatic nerve and its branches and the phrenic nerve. Axonal sprouts are abundant. There is no evidence of demyelination, and unaffected nerve fibers are normally myelinated. Sensory axons are spared. Almost all distal motor axons have disappeared in four to five weeks after birth. Ventral nerve roots show a reduced diameter of the largest fibers but no fiber deficits. The ventral horn cells show slight chromatolysis. The corticospinal tract is normal, but in terminally ill animals the fasciculus gracilis, the rubrospinal tract and possibly also reticulospinal fibers degenerate. The brain is histologically normal. The disease manifests itself in a dying-back fashion in the distal portion of the motor neurons and may represent an animal model of hereditary motor neuron diseases in man.

NAD and axon degeneration: From the Wlds gene to neurochemistry

“…3 In motor degenerative diseases and peripheral nerve diseases caused by toxic insults, the axons of the unhealthy neurons develop a 'dying-back' phenomenon, which starts from the distal terminal and progressively spreads toward the cell body, before death of the cell body. 4,5 Axonal degeneration also represents a major pathological feature in epilepsy, ischemia and aging as reported in the following publications. 6,7 The common morphological changes that occur during axon degeneration include axonal beading or focal swelling followed by axon fragmentation.…”

Trophic Support of Motoneurons: Physiological, Pathophysiological, and Therapeutic Implications

“…Pmn mice show a strictly programmed, progressive .degeneration of motoneurons starting at the hind legs, progressing to the forelegs, and finally also affecting the motor nuclei of the brain stem, including the facial motor nucleus (91,95). The transection of the facial nerve in pmn mice 2 weeks after the first clinical signs of motoneuron degeneration (hind legs) did not result in an enhanced but a delayed progression of facial motoneuron degeneration.…”

“…These include protection of motoneurons against lesion effects and protective effects on the progression of degenerative changes in animal mutants such as the pmn mouse (91), which exhibits characteristics similar to ALS (15) , the mnd mouse (61,62), and the wobbler mutant (22,43,82), in which the paretic manifestations become apparent predominantly in the forelegs and do not reach levels as extreme as those in the case of the pmn mutant (91). Very recently, transgenic mice with a neuron-specific overexpression of light and heavy neurofilament chains have been created (16 , 106) which show morphological changes of myelinating axons with similarities to the pathological picture of ALS patients (15).…”

An Inhibitor of Serine Proteases, Neuroserpin, Acts as a Neuroprotective Agent in a Mouse Model of Neurodegenerative Disease

“…Myelinated fibers in the phrenic nerve that innervate the diaphragm have been reported to be severely affected in pmn/pmn mice, suggesting that these mice die by respiratory failure (Schmalbruch et al, 1991). To determine whether neuroserpin overexpression prevented this loss, myelinated axons were counted in the phrenic motor nerve at the end stage of disease (40 d of age) in pmn/pmn, pmn/pmn;ThyNs, and control littermates.…”

“…pmn/pmn mice are characterized by a "dying-back" motor neuronopathy (Schmalbruch et al, 1991); the pathophysiology begins in the axon terminals by an unknown process, followed by a degeneration of the motoneuron cell bodies. We first show that the activity of PA is increased in sciatic nerves and spinal cord of pmn/pmn mice compared with controls.…”