Axonal degeneration of ascending sensory neurons in gracile axonal dystrophy mutant mouse

Abstract

The distribution of axonal spheroids was examined in the central nervous system of gracile axonal dystrophy (GAD) mutant mice. Only few spheroids are observed in the gracile nucleus of the medulla in normal mice throughout the period examined, while they are first noted in GAD mice as early as 40 days after birth. The incidence of spheroids shifts from the gracile nucleus to the gracile fasciculus of the spinal cord with the progress of disease, suggesting that the degenerating axonal terminals of the dorsal ganglion cells back from the distal presynaptic parts in the gracile nucleus, along the tract of the gracile fasciculus, toward the cell bodies in the dorsal root ganglion. This phenomenon indicates that the distribution of spheroids is age dependent and reflects a dying-back process in degenerating axons. In addition to the gracile nucleus and the gracile fasciculus, which is one of the main ascending tracts of primary sensory neurons, it was noted that the other primary sensory neurons joined with some of the second-order neurons at the dorsal horn and neurons at all levels of the dorsal nucleus (Clarke's column) are also severely affected in this mutant. The incidence of the dystrophic axons are further extended to the spinocerebellar tract and to particular parts of the white matter of the cerebellum, such as the inferior cerebellar peduncle and the lobules of I-III and VIII in the vermis. These results indicate that this mutant mouse is a potential animal model for human degenerative disease of the nervous system, such as neuroaxonal dystrophy and the spinocerebellar ataxia.

Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration

“…The gad mouse has been reported to suffer from a progressive neurological phenotype characterized by development of tremor and sensory ataxia at around 3 mo of age postnatally, followed by motor ataxia and ultimately leading to mortality. Neuropathological findings included nerve fiber loss with astrocytic proliferation and considerable axonal swellings in the gracile fascicles of the spinal cord along with axonal degeneration and formation of spheroid bodies in the nerve terminals (16,18,19). Similarly, recently generated Uchl1 KO mice have been shown to suffer from markedly impaired synaptic transmission at the neuromuscular junction accompanied by structural defects such as loss of synaptic vesicles and accumulation of tubulovesicular structures at the presynaptic nerve terminals in addition to denervation of the muscles (15).…”

Localization of Ubiquitin C-Terminal Hydrolase L1 in Mouse Ova and Its Function in the Plasma Membrane to Block Polyspermy

“…We used 8-week-old BDF1, gad (CBA/RFM), 23,24 and Uchl3 knockout (C57BL/6J) 12,25 female and male mice. BDF1 mice were purchased from Nihon SLC, Inc. (Hamamatsu, Japan).…”

Behavioral Study on the Gracile Axonal Dystrophy (GAD) Mutant Mouse

“…Pathologically, in the central nervous system the dorsal column, the dorsal spinocerebellar, pyramidal, and spinal trigeminal tracts are affectted [4,6,10,11] . Focally swollen axons or spheroids, which are characteristic of GAD mice, are observed in these affected tracts in addition to nerve fiber loss and gliosis.…”

“…Beginning at about 3 weeks of age, the [7]. We believe that GAD mice can serve as an animal model for spinocerebellar degeneration (ataxia), particularly Friedreich's ataxia, and CharcotMarie-Tooth disease (hereditary motor and sensory neuropathy) in humans [4,7,11] .…”

“…The f asciculus gracilis of the dorsal column degenerates first and most severely in GAD mice, beginning at about 4 weeks of age. Moreover, spheroids are observed in the gray matter of the lumbar cord particularly the dorsal part, where A o and C fibers terminate [1], from about 11 of weeks age onwards [4]. The reduction in latencies may be related to dysfunction or degeneration of collaterals of primary of f erents controlling the transmission of nociceptive information in the f asciculus gracilis.…”