Molecular Basis of Mitochondrial Dysfunction in Neurodegeneration - Alzheimer's disease is the most frequent form of dementia that is characterized by progressive memory loss
and cognitive dysfunction. Mutations in presenilins are the most common cause of early onset familial
Alzheimer's disease. Although altered presenilin function has been known to have a role in Alzheimer's
disease for more than 20 years, the functional consequences of mutations in presenilins are controversial and
not understood. Due to the complexity in understanding presenilin function, we are using a simple model
system, Caenorhabditis elegans, to uncover the in vivo biological role of presenilins. We have discovered that
mutations in sel-12, which encodes a C. elegans presenilin ortholog, leads to increased transfer of
endoplasmic reticulum calcium to the mitochondria, which results in a concomitant increase in mitochondrial
respiration and superoxide production. Furthermore, we have demonstrated that the neurodegeneration that
develops in sel-12 mutants is caused at least in part by this increase in mitochondrial superoxide production.
We hypothesize that presenilin mutations lead to increased endoplasmic reticulum – mitochondria contact and
communication that results in altered mitochondrial function that negatively impacts neuronal health. We will
take a multifaceted approach to test this hypothesis. First, we will define the role presenilin and calcium have in
mediating endoplasmic reticulum – mitochondria interaction dynamics. Second, we will determine the role
mTOR signaling has in promoting neurodegeneration in presenilin mutants. Third, we will determine the role
presenilin mutations associated with familial Alzheimer's disease have in mitochondria function and
neurodegeneration. Lastly, we will identify key gene products that help mediate the elevated endoplasmic
reticulum to mitochondria calcium transfer observed in presenilin mutants. Knowledge gained from the study of
presenilin function in C. elegans should provide novel insight into the mechanisms underlying Alzheimer's
disease and may lead to novel therapeutic strategies for treating Alzheimer's disease.
