AXONAL TRANSPORT IN PERIPHERAL NERVE DISEASE

Project: Research project

Description

Intensive investigation of the pathophysiology of axonal transport
continues, emphasizing the model and sensory neuropathy induced
in rats by systemic treatment with p-bromophenylacetylurea
(BPAU). Results obtained during the previous funding period show
that BPAU neuropathy is associated with abnormalities in the
turnaround and recirculation of endogenous proteins by rapid
retrograde transport. These findings are significant because
turnaround-defects could cause the distal tubulomembranous
axonal lesions that characterize BPAU neuropathy. Furthermore,
the turnaround-abnormality occurs before other signs of nerve
damage and is commensurate with the severity of the pathology.
Current results show that BPAU causes another striking effect in
motor nerve cells, namely a marked shortening in the onset of
rapid transport. We will test the hypothesis that the shortened
transport-onset reflects a disturbance in the processing of
particles being assembled for delivery into the axon. Three
groups of experiments are planned. First we intend to determine
whether the onset-effect is uniquely caused by the neurotoxic
ureides related to BPAU and to discover whether the dose-effect
is uniquely caused by the neurotoxic ureides related to BPAU and
to discover whether the dose-effect relations are compatible with
a pathogenic role. These experiments make use of a series of
BPAU analogues, locally synthesized for the purpose. The second
set of experiments will analyze in detail the effect of BPAU on
the kinetics of particle transport and transport-turnaround. This
work takes advantages of recent advances in optical methods and
image-processing for real-time analysis of particle motion. The
third set of experiments will explore the possibility that BPAU
treatment leads to detectable changes in the biochemical and
immunochemical properties of fast transported organelles. This
work involves the application of a set of monoclonal antibodies
generated in this laboratory to the surface antigens of intra-
axonal organelles from rat nerve. Overall we expect to add
significantly to understanding of the pathogenesis of toxicant-
induced, dying-back neuropathies.
StatusFinished
Effective start/end date4/1/823/31/95

Funding

  • National Institutes of Health
  • National Institutes of Health: $145,135.00
  • National Institutes of Health
  • National Institutes of Health: $164,152.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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Axonal Transport
Peripheral Nervous System Diseases
Organelles
Protein Transport
Surface Antigens
Axons
Pathology
Neurons
4-bromophenylacetylurea

ASJC

  • Medicine(all)
  • Neuroscience(all)