IPN Dissertation Defense: Patricia Sinclair

Age and cholinergic mechanisms of mitochondrial signaling and toxicity.

PhD candidate in Neuroscience: Patricia Sinclair
Committee: Prof. Nadine Kabbani (dissertation director), Prof. Saleet Jafri, Prof. Karl Fryxell, Prof. Jim Olds 

Abstract:

Aging is a physiological process that entails physical and cognitive change however why some people experience age-related dementia due to neurodegeneration is not well understood. The most common form of neurodegeneration is non-familial, sporadic, Alzheimer’s disease (AD) that is highly associated with aging. AD is also significantly higher in women than in men. Neurodegeneration of acetylcholine producing neurons, involved in memory and cognition, is a known hallmark in early AD and most FDA-approved medications operate as restorative pro-cholinergic drugs. In addition to the cholinergic deficit, AD is associated with the buildup of various amyloid type proteins (amyloid-beta and tau) within the brain. Studies show elevated levels of the neurotoxic amyloid beta 42 (A𝛽42) within the brain of AD patients. A𝛽42 appears to bind many cellular targets but recent compelling evidence points to an important role of altered mitochondrial function in amyloid-mediated neurodegeneration. This study uses mass spectrometry proteomics, bioinformatics, and functional cellular assays to uncover A𝛽42 mediated damage to neuronal mitochondria. Using whole-cell proteomic analysis I demonstrate specific changes in mitochondrial protein pathways in response to A𝛽42. In addition, I examine the involvement of the 𝛼7 nAChR in mitochondrial responses to A𝛽42 and test the effect of estrogen withdrawal on mitochondrial health and function. The overall findings indicate an important role for mitochondrial proteins in homeostatic responses to A𝛽42 presentation and suggest an important role for estrogen signaling in mitochondrial neuroprotection.