Axonal Transport Defects in Neurodegenerative Diseases

Abstract

Adult-onset neurodegenerative diseases (AONDs) comprise a heterogeneous group of neurological disorders characterized by a progressive, age-dependent decline in neuronal function and loss of selected neuronal populations. Alterations in synaptic function and axonal connectivity represent early and critical pathogenic events in AONDs, but molecular mechanisms underlying these defects remain elusive. The large size and complex subcellular architecture of neurons render them uniquely vulnerable to alterations in axonal transport (AT). Accordingly, deficits in AT have been documented in most AONDs, suggesting a common defect acquired through different pathogenic pathways. These observations suggest that many AONDs can be categorized as dysferopathies, diseases in which alterations in AT represent a critical component in pathogenesis. Topics here address various molecular mechanisms underlying alterations in AT in several AONDs. Illumination of such mechanisms provides a framework for the development of novel therapeutic strategies aimed to prevent axonal and synaptic dysfunction in several major AONDs.

Molecular chaperone Hsp110 rescues a vesicle transport defect produced by an ALS-associated mutant SOD1 protein in squid axoplasm

“…The mutant protein is proposed to activate the MAPK cascade via an interaction with a component(s), designated X, that activates ASK1 that, in turn, inhibits anterograde transport via p38-mediated phosphorylation of kinesin heavy chain (KHC). Such phosphorylation has been detected in another study of a mutant SOD1 in squid axoplasm (34). Notably, the phosphorylation of KHC is not detectable on immunoblots, requiring instead addition of [ 32 P]ATP to the axoplasm, followed by immunoprecipitation (G. Morfini, Y.S.…”

“…G85R SOD1YFP Activates p38 MAPK in Squid Axoplasm. Studies of fast axonal transport in squid axoplasm in the presence of H46R SOD1 and oxidized SOD1, as well as other neurodegenerationassociated proteins, have associated transport defects with activation of various kinase cascades (34). In the case of SOD1, such transport defects are associated with phosphorylation of p38 MAPK, which stimulates its kinase activity (33).…”

Deficits in axonal transport precede ALS symptoms in vivo

“…Consistently, several lines of evidence suggest that deficits in both anterograde and retrograde transport contribute to ALS pathogenesis (3,4,10,(15)(16)(17)(18)(19)(20)(21)(22)(23). ALS patients and mice expressing mutant superoxide dismutase 1 (SOD1) display neurofilament accumulations, which may derive from defects in slow anterograde transport (19,24,25).…”

“…Neurons rely on anterograde transport for the movement of structural components and newly formed organelles along the axon and on retrograde transport for the transfer of organelles and ligands from synapses to the soma (1). Deficits in axonal transport have been proposed to contribute to the degeneration of motor and sensory neurons (2)(3)(4). For example, postnatal disruption of the microtubule-dependent motor KIF5A induces a reduction in slow anterograde transport, resulting in accumulation of neurofilaments in dorsal root ganglion (DRG) cell bodies, reduction in axonal caliber, and degeneration of sensory neurons (5).…”

Quantitative Analysis of Axonal Transport by Using Compartmentalized and Surface Micropatterned Culture of Neurons

“…Yet, it is not fully understood that Aβ can trigger the impairment of mitochondrial transport as a mechanism underlying dysfunction of neural activities in neurodegenerative process. 2,12 A natural approach to investigating these questions is to measure the morphology, locations, and movements (retrograde vs anterograde) of mitochondria in healthy neurons and compare such measurements to neurons that are in a diseased state. Tracking analysis requires single, intact neurons to be selected and the mitochondrial movement analyzed taking into account the complexity of mitochondrial dynamics including the rapid changes in direction and fusion/fission events.…”