Calcium, a versatile signaling molecule, is a critical mediator of many cellular processes, including muscle contraction, transcription, cell division, and synaptic vesicle release. Paradoxically, calcium can also trigger cell death and cellular necrosis. Therefore, dysregulation in calcium signaling can affect cells in different ways and to varying degrees. Consequently, calcium levels need to be tightly controlled. Indeed, defective calcium signaling has been implicated in many neurodegenerative diseases, muscular dystrophies and heart disease. To understand the regulation of calcium signaling, we are exploiting the model system Caenorhabditis elegans to identify critical components that are involved in the regulation of calcium handling. From our non-biased genetic studies, we have found a novel role for a conserved protein, SEL-12, in endoplasmic reticulum calcium handling which is critical for mitochondria morphological organization and function. SEL-12 is the C. elegans homolog of presenilin. Mutations in presenilins are the most common cause of early onset familial Alzheimer's disease. Despite the identification of the involvement of presenilin in Alzheimer's disease over 20 years ago, the functional consequences of mutations in presenilin are not understood. Here, we propose to examine the function of SEL-12 in C. elegans to understand its role in calcium handling and mitochondrial activity and gain insight into Alzheimer's disease pathology. Thus, using the strengths of the C. elegans, we are taking a multifaceted approach utilizing live cell imaging in concert with genetic, molecular and cell biology techniques to test the following hypothesis: Presenilin/SEL-12 functions to regulate endoplasmic reticulum calcium signaling and that in the absence of presenilin/SEL-12 function calcium transfer to the mitochondria is increased impacting mitochondrial function and cellular fitness. We believe our studies will provide novel understanding into the mechanisms that arise in Alzheimer's disease and will, therefore, provide unique insight into the development of new therapeutic strategies for Alzheimer's disease.

Public Health Relevance

Deregulation of calcium handling and mitochondrial function is implicated in most if not all neurodegenerative diseases. Thus, the goal of this project is to resolve the molecular mechanisms underlying calcium regulation and mitochondrial function and, therefore, provide insight into the causes of and strategies to treat neurodegenerative disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM088213-06A1
Application #
9176764
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Nie, Zhongzhen
Project Start
2010-07-01
Project End
2020-07-31
Budget Start
2016-09-15
Budget End
2017-07-31
Support Year
6
Fiscal Year
2016
Total Cost
$295,072
Indirect Cost
$90,439
Name
Albany Medical College
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
190592162
City
Albany
State
NY
Country
United States
Zip Code
12208