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Free keywords:
Axonal transport, transport
defects, neurodegeneration, autophagy,
FEZ1, Kinesin, Syntaxin, Munc18,
SNARE, synapse
Abstract:
Formation and normal function of
neuronal synapses are intimately
dependent on the delivery to and removal
of biological materials from synapses by
the intracellular transport machinery.
Indeed, defects in intracellular transport
contribute to the development and
aggravation of neurodegenerative disorders.
Despite its importance, regulatory
mechanisms underlying this machinery
remain poorly defined. We recently
uncovered a phosphorylation-regulated
mechanism that controls FEZ1-mediated
Kinesin-1 based delivery of Stx1 into neuronal
axons. Using C. elegans as a model
organism to investigate transport defects,
we show that FEZ1 mutations resulted in
abnormal Stx1 aggregation in neuronal
cell bodies and axons. This phenomenon
closely resembles transport defects
observed in neurodegenerative disorders.
Importantly, diminished transport due
to mutations of FEZ1 and Kinesin-1
were concomitant with increased accumulation
of autophagosomes. Here, we
discuss the significance of our findings
in a broader context in relation to regulation
of Kinesin-mediated transport and
neurodegenerative disorders.
