|dc.description.abstract||The compartmental hypothesis of neurodegeneration proposes that the neurone, long
recognized to consist of morphologically and functionally distinct compartments, also
houses distinct degeneration mechanisms for the soma, axon and nerve endings.
Support for this hypothesis is provided by the phenomenon of the WldS (for Wallerian
Degeneration, slow) mouse, a mutant in which axons survive several weeks after
transection, rather than degenerating within 24-48 hours as in wild type mice, by
virtue of expression of a chimeric Nmnat1/Ube4b protein. In this thesis I used the WldS-mouse to re-examine and extend the theory of compartmental neurodegeneration
by focusing specifically on sensory axons and endings; and finally by considering a
fourth compartment, the dendrites.
The first part of this thesis reports that Ia afferent axons and their annulospiral endings
are robustly protected from degeneration in WldS mice. Homozygous or heterozygous
WldS mice crossbred with transgenic mice expressing fluorescent protein in neurones
were sacrificed at various times after sciatic nerve transection. Fluorescence
microscopy of whole mount preparations of lumbrical muscles in these mice revealed
excellent preservation of annulospiral endings on muscle spindles for at least 10 days
after axotomy. No significant difference was detected in the protection with age or
gene copy-number in contrast to the protection of motor nerve terminals, which
degenerate rapidly in heterozygote and aged homozygote WldS mice.
In an attempt to explain the difference in motor and sensory protection by WldS, examination of three hypotheses was undertaken: a) differences in protein expression,
tested by western blot and immunohistochemistry; b) differences in the degree of
neuronal branching, tested through examination of g-motor axons and endings which
have a degree of branching intermediate to motor and sensory neurons; and c)
differences in the activity in the disconnected stumps, through primary culture of the
saphenous and phrenic nerve, selected because they comprise largely pure sensory
and motor axons respectively. The data suggest that none of these hypotheses
provides a sufficient explanation for the difference between sensory and motor
protection by WldS.
The last part of this thesis attempts to extend the theory of compartmental
degeneration. I examine a system for investigation of WldS-mediated protection of
dendrites. In preliminary experiments retinal explants from transgenic mice
expressing YFP in a subset of retinal ganglion-cell neurones were cultured. The
dendritic arbours of these cells were shown to be amenable for repeated visualization
and accessible to injury and monitoring of degeneration.
Overall the data in this thesis suggest that the level of WldS -mediated protection
conferred to an axon or axonal endings varies between different neuronal types. This
has implications for the potential applications of WldS research to clinical problems.
Specifically, the data imply that sensory neuropathies may benefit more than motor
neuropathies from treatments based on the protective effects of WldS. These findings
in sensory neurones also challenge some of the assumptions made about WldS-
mediated protection of neurones, for example the extent of the age-effect on axonal
endings. Further investigation of WldS-mediated protection in the CNS could give
renewed impetus to attempts to discover targets for treatment in common
neurodegenerative diseases. Finally, a system for investigation of dendritic
degeneration has been piloted, suggesting that molecules involved in the degeneration
of dendrites or in protection from this degeneration may be amenable to investigation
in this system, prospectively extending the compartmental hypothesis of neuronal