Co-occurring PAM-1 and PTL-1 mutations exacerbate neurodegeneration in C. elegans.
Academic Level at Time of Presentation
Senior
Major
Biology
Minor
Chemistry
List all Project Mentors & Advisor(s)
Chris Trzepacz, PhD
Presentation Format
Oral Presentation
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 they 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 ptl-1 mutations. Data collected in the present study showed an accelerated onset of neurodegeneration for adult C. elegans that harbored both pam-1 ptl-1 mutations relative to worms that contained either a single pam-1 or ptl-1 mutation. These data did not support the interaction of PAM-1 and PTL-1 in governing neurodegeneration in C. elegans; instead, these data suggested independent mechanisms are simultaneously driving neurodegeneration, resulting in the observed accelerated neurodegenerative phenotypes. However, 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.
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Honors College Senior Thesis Presentations
Co-occurring PAM-1 and PTL-1 mutations exacerbate neurodegeneration in C. elegans.
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 they 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 ptl-1 mutations. Data collected in the present study showed an accelerated onset of neurodegeneration for adult C. elegans that harbored both pam-1 ptl-1 mutations relative to worms that contained either a single pam-1 or ptl-1 mutation. These data did not support the interaction of PAM-1 and PTL-1 in governing neurodegeneration in C. elegans; instead, these data suggested independent mechanisms are simultaneously driving neurodegeneration, resulting in the observed accelerated neurodegenerative phenotypes. However, 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.