Molecular Mechanisms of Axonal Transport

University Of Illinois At Chicago, Chicago IL

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Abstract

Fast axonal transport (FAT) of membrane-bounded organelles (MBOs) is critical for neuronal growth, maintenance and regeneration. Changes in delivery of critical cargos by FAT can affect neuronal functions that include synaptic transmission, action potentials and neurotrophin supply. If these are chronically compromised, the result can be a dying back neuropathy leading to loss of synaptic connections and eventually to the death of affected neurons. Although the molecular pathology of these diseases may be complex and multifactorial, reductions in FAT are sufficient to produce a distal axonopathy in diseases like hereditary spastic paraplegia and disruption of FAT are documented components of pathogenesis in other neurodegenerative diseases, including Alzheimer's (AD) and Huntington's (HD) disease, among others. Thus, study of molecular mechanisms for FAT provides insight into normal and pathological neuronal functions. Studies of FAT in isolated axoplasm from squid led to our discovery of kinesins and subsequently to the identification of specific regulatory pathways for FAT, which were confirmed in mammalian models. Experiments proposed in this application extend our ongoing studies on molecular mechanisms of FAT in three areas. First, we propose to map isoform-specific regulation of kinesin-based transport that allows delivery of membrane protein cargos to different functional microdomains. As specific pathways were identified, some affected only a subset of kinesin-1 motors. Experiments under this aim will determine physiological roles for different kinesin isoforms and how they can be differentially regulated. Second, we propose that specific kinesin-1 isoforms are associated with different membrane protein cargos. The existence of distinct kinesin-1 isoforms suggests that they may have distinct functional roles in the neuron, so inhibition of one isoform may affect a subset of cargo proteins, providing a mechanism for targeting a specific set of cargos to a particular functional domain (i.e. presynaptic terminal, node of Ranvier, etc.). Experiments in this aim will examine how specific kinesin-1 isoforms become associated with different transport vesicles and characterize those vesicles. Third, we propose that kinase pathways activated by pathogenic proteins affect the transport of specific membrane protein cargos critical for neuronal function and survival. Experiments in this aim will determine if these changes are necessary and sufficient to produce the distal axonopathy and eventual death of affected neurons in two different categories of neurodegeneration. We propose to evaluate the role of kinesin-1 isoforms and cytoplasmic dynein in pathogenesis of Huntington's and other polyQ expansion diseases, where kinases activated by pathogenic polyQ proteins compromise kinesin-mediated motility in affected neurons. Planned experiments will define relevant pathways and their activation by pathogenic polyQ proteins. Similarly, we will evaluate the ability of axonal Aβ42 oligomers to act in axonal compartments through activation of axonal kinases. Taken together, these proposed studies will illuminate the roles for kinesin-1 in both normal function and neuropathology.