Date on Honors Thesis

Spring 4-24-2026

Major

Biology

Minor

Chemistry

Examining Committee Member

Dr. Chris Trzepacz

Examining Committee Member

Dr. Ricky Cox

Examining Committee Member

Dr. Dena Weinberger

Abstract/Description

Debilitating neurodegenerative conditions are increasingly prevalent in our aging population, yet treatment options remain limited. Though neurodegenerative diseases vary in pathophysiology and clinical manifestations, these diseases are related to one another in that many involve misfolded proteins. Tau is a member of the microtubule-stabilizing MAPT/MAP2/MAP4 family, and misfolded tau proteins form the neurotoxic aggregates called neurofibrillary tangles (NFTs) found in the brains of patients with Alzheimer's disease and other neurodegenerative diseases. Designing a study to elucidate the neurotoxic role of tau is difficult because other MAPs may have compensatory mechanisms which confound study data. Caenorhabditis elegans (C. elegans) is frequently utilized as a model organism for neurodegenerative disease because of its ease of maintenance, transparency, simple yet invariant neuroanatomy, and homology to the human genome. The C. elegans genome contains a single MAPT/MAP2/MAP4 family homolog called PTL-1, and C. elegans that lack PTL-1 function display an earlier onset of neurodegeneration. Another protein of interest is the puromycin-sensitive aminopeptidase (PSA). PSA is conserved in all multicellular organisms, although its role is not well characterized. The C. elegans homolog of PSA, PAM-1, has been shown to affect embryogenesis and reproduction. Recent work in the Trzepacz lab has shown that worms that lack PAM-1 function also display accelerated onset of neurodegenerative phenotypes. Furthermore, transgenic studies using mice and flies in other labs have demonstrated that tau and PSA interact genetically, and that PSA may play a protective role in tau-induced neurodegeneration. In order to examine the relationship between PAM-1 and PTL-1, we used a GFP transgene to monitor neurodegeneration in vivo in adult C. elegans that harbored single pam-1, single ptl-1, or both pam-1 and ptl-1 mutations. Data collected in the present study showed an accelerated onset of neurodegeneration for adult C. elegans that harbored both pam-1 and ptl-1 mutations relative to worms that contained either a single pam-1 or ptl-1 mutation. These data do not support a relationship between PAM-1 and PTL-1 like that of PSA and tau; instead, data suggested three different conclusions. The first is that PTL-1 may not be aggregating. The second is that PAM-1 may not be neuroprotective of PTL-1 aggregation if PTL-1 does aggregate. The third is that if PTL-1 does aggregate and PAM-1 is neuroprotective, we cannot rule out the possibility that the investigation into a neuroprotective role of PSA homologs in ameliorating tau aggregation may be compromised in the C. elegans model due to the destabilizing effect of removing the sole homolog of the microtubule-stabilizing MAPT/MAP2/MAP4 family. Data collected in the study better characterize interactions between two elusive proteins, PAM-1 and PTL-1, and provide context for using C. elegans as a model organism for tauopathies.

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