Loss of translation elongation factor eEF1A2 differentially affects pathways responsible for dying-back neuropathy and Wallerian degeneration in vivo

L. M. Murray, Derek Thomson, A. Conklin, Thomas. M. Wishart, T. H. Gillingwater

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract / Description of output

Mechanisms regulating neuronal viability are highly compartmentalized within neurons, with distal compartments – axons and
synapses – being particularly vulnerable to a range of neurodegenerative stimuli. Numerous compartment-specific cellular
pathways can bring about axonal and synaptic degeneration. For
example, Wallerian degeneration, originally described as the
response to traumatic nerve injury, is characterized by rapid,
synchronous fragmentation (normally complete within 12–24 h)
and organelle depletion. In contrast, dying-back neuropathies,
commonly associated with conditions such as motor neuron disease,
are characterized by a slower, progressive distal to proximal neuronal
withdrawal in the presence of intact organelles. Despite distinct
morphological characteristics, the convergent or divergent molecular
mechanisms underlying these neurodegenerative pathways remain
elusive. In this study, we examined neurodegenerative mechanisms
in the naturally occurring ‘wasted’ mutant mouse which carries a
null mutation in the gene encoding elongation factor eEF1A2, an
isoform of eEF1A. This mutation disrupts protein synthesis specifi-
cally in adult neurons and muscle, and has previously been shown
to induce degeneration of lower motor neurons. Using highresolution analysis of synaptic and axonal morphology we show
that neurodegeneration in Wasted mice occurs by a ‘dying-back’
mechanism, morphologically distinct from Wallerian degeneration.
We show that dying-back pathology in Wst mice cannot be
accounted for by downstream reductions in levels of Smn protein
(known to interact with eEF1A proteins and cause dying-back pathology
in spinal uscular atrophy). However, levels of the zinc finger protein ZPR1 were modestly reduced to a similar level in Wst mice and
;SMN2 mice (a model of spinal muscular atrophy) suggesting
that ZPR1 may play a common role in regulating dying-back pathways.
Surprisingly, we also found that Wallerian degeneration was almost
completely absent 24 h after an experimental nerve lesion in Wasted
mice. This work demonstrates that Wallerian degeneration and
dying-back neuropathy occur via divergent mechanisms in vivo
with differing responses to disruption of eEF1A2 expression.
Furthermore, eEF1A2-dependent molecular cascades are required
for the normal initiation and progression of WD, supporting the
hypothesis that WD is an active rather than a passive process.
Original languageEnglish
Title of host publicationProceedings of the Anatomical Society of Great Britain and Ireland
Subtitle of host publicationThe Summer Meeting of the Anatomical Society took place on 2–4 July 2008 at the new Jubilee Campus, University of Nottingham, UK
Number of pages1
Publication statusPublished - May 2009


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