Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Molecular Cell Biology

Language

English (en)

Date of Award

January 2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Jeffrey Milbrandt

Abstract

Axonal degeneration is a prominent feature of many neurological disorders including Parkinson's disease: PD), motor neuron disease, inherited, diabetic, and drug-induced peripheral neuropathies. It is now thought that axonal degeneration is an active process, due in large part to studies of the Wlds mutant mouse, which undergoes delayed Wallerian degeneration in response to axonal injury. Wlds mice have slower disease progression in numerous models of neurodegenerative diseases. The Wlds mutation results in the production of a chimeric protein that containing nicotinamide mononucleotide adenylyltransferase 1: Nmnat1). Increased expression of Nmnat isoforms are sufficient for axonal protection in vitro and in vivo. We attacked axonal degeneration from three directions. First, a common finding in neurodegenerative disorders with axonal degeneration is mitochondrial dysfunction. We found that mitochondrial inhibition, via rotenone, induced profound axonal degeneration in dorsal root ganglia neurons; however, this degeneration was delayed by expression of Nmnat. Nmnat decreased axonal accumulation and sensitivity to reactive oxygen species, but did not affect the rate of ATP loss. Second, it has also been demonstrated that inhibition of the mixed lineage kinases: MLKs) can inhibit not only neuronal death, but loss of axonal terminals in models of neurological disorders, including PD. We found that the loss of dual leucine zipper kinase: DLK) or inhibition of its downstream target, JNK, decreases the rate of axonal degeneration in vitro . Finally, purine nucleosides are known to have trophic effects on neurons and can stimulate axonal growth and regeneration. Guanosine has been used in vivo to decrease injury in both models of stroke and spinal cord injury. We found that both adenosine and guanosine robustly slow axonal degeneration in vitro while inosine does not. Adenosine is protective when added previous to, immediately following, or up to 6 hr after the injury suggesting that it has a local mechanism of action on components of axonal degeneration likely downstream of JNK activation. The protection lasts several days, but is halted by removal of adenosine demonstrating its necessity during protection. This armamentarium of axonal degeneration inhibitors will provide new avenues for understanding disease and therapy development.

Comments

Permanent URL: http://dx.doi.org/10.7936/K7SB43RF

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