Publication Date




Embargo Period


Degree Type


Degree Name

Doctor of Philosophy (PHD)


Molecular and Cellular Pharmacology (Medicine)

Date of Defense


First Committee Member

R. Grace Zhai

Second Committee Member

Antonio Barrientos

Third Committee Member

Mario Saporta

Fourth Committee Member

Fangliang Zhang

Fifth Committee Member

Helmut Kramer


Age-related neurodegenerative diseases affect millions of people worldwide. The increasing number of these disabling and currently incurable neurodegenerative diseases have devastating impacts on the affected individuals and families. However, current mechanistic understanding of the pathogenesis of neurodegenerative disorders remains limited, and neuroprotective strategies combating neurodegeneration are lacking. My lab has previously identified a potent neuronal maintenance factor nicotinamide mononucleotide adenylyltransferase (NMNAT), an evolutionarily conserved nicotinamide adenine dinucleotide (NAD+) synthase and neuroprotective factor that protects against proteinopathies through regulating protein homeostasis. In Drosophila, the Nmnat gene can be alternatively spliced into two mRNA variants, RA and RB, which produce two protein isoforms, PC and PD, with distinctive subcellular localizations and are differentially regulated under stress conditions. However, their neuroprotective capacities in neurodegenerative diseases are largely unknown. In this project, I demonstrate that Drosophila Nmnat isoforms PC and PD have divergent protective capacities in neurodegenerative diseases. In Drosophila models of Huntington’s disease (HD), neuronal compartment-specific accumulation of mutant Htt aggregates causes neurotoxicity. I show that Nmnat-PC and PD are differentially regulated and have divergent neuroprotective capacities in HD. Nmnat-PC has robust protective capacity in glia, but minimal protection in neuron, while Nmnat-PD protects against mutant Htt-induced cytotoxicity in both neurons and glia. Specifically, neuronal overexpression of Nmnat-PD reduces progressive accumulation of thioflavin S-positive, amyloid-like mutant Htt aggregates, neutralizes the adhesiveness of the aggregates, and inhibits the clustering of mutant Htt with mitochondria and synaptic proteins, thereby restoring neuronal function. Partial loss of endogenous Nmnat exacerbates mutant Htt-induced neurodegeneration through enhancing mutant Htt aggregation and adhesive property. Conditional expression of Nmnat-PD after the onset of degenerative phenotypes significantly delays the progression of neurodegeneration, revealing the therapeutic potential of Nmnat-PD-mediated neuroprotection at advanced stages of HD. In tauopathy models, both Nmnat-PC and PD are recruited to hyperphosphorylated Tau (pTau)-induced vacuoles in the brain. Nmnat-PD reduces pTau-induced locomotor defects and brain apoptosis, likely through promoting the clearance of pTau in the brain, while Nmnat-PC has minimal protective effects. Moreover, Nmnat-PD reduces p-Tau induced mitochondrial clustering, synaptic cytomatrix protein loss, and F-actin accumulation. My findings provide mechanistic understandings of how toxic protein species (mutant Htt and pTau) promote neurodegeneration, shed light on how neurons achieve self-protection against adverse conditions by producing functionally different protein isoforms, and will further assist the development of therapeutic interventions to reduce disease progression.


Neurodegeneration; Nmnat; Drosophila; Huntington’s disease; Tauopathy

Available for download on Sunday, October 17, 2021