Defense Date

11-2-2015

Availability

Worldwide Access

Submission Type

dissertation

Degree Name

PhD

Department

Pharmacology

School

School of Pharmacy

Committee Chair

Rehana Leak

Committee Member

Paula Witt-Enderby

Committee Member

Lauren O'Donnell

Committee Member

Sandra Hewett

Committee Member

Wilson Meng

Keywords

Adaptation, Aging, Astrocyte, Glutathione, N-Acetyl Cysteine, Proteotoxicity

Abstract

Neurodegenerative disorders such as Parkinson's and Alzheimer's disease are projected to affect 15.14 million people by the year 2050. All neurodegenerative diseases are characterized by protein-misfolding stress, or proteotoxicity, in both neurons and glia. However, the impact of proteotoxicity on glia is less well understood than in neurons. Astrocytes are an abundant type of glia and play an essential role in brain homeostasis by supporting neuronal functions. Therefore, one of the major goals of the present study was to identify ways to reduce the impact of proteotoxicity in astrocytes. In Aim 1, we examined natural adaptations to proteotoxic stress in astrocytes. Our studies demonstrate that the astrocytes surviving a severe proteotoxic insult are resistant to subsequent challenges due to upregulation of the antioxidant biomolecule glutathione. Prior to this body of work, only mild stressors were thought to elicit stress tolerance and severe stress was thought to only weaken cells. In contrast with traditional views of reactive astrocytes, severely stressed astrocytes were still able to protect neighboring neurons from proteotoxic injury in our model. In Aim 2, we examined the therapeutic potential of N-acetyl cysteine, a glutathione precursor known to benefit patients with neurological disorders. We discovered that N-acetyl cysteine protected astrocytes from proteotoxic stress independent of glutathione. Instead, the protection afforded by N-acetyl cysteine was abolished by heat shock protein inhibitors, suggesting a novel mechanism of action for N-acetyl cysteine in astrocytes. It is important to promote heat shock protein activity in patients with neurodegenerative conditions because loss of chaperone defenses may contribute to proteotoxicity in the elderly. In Aim 3, we characterized the impact of aging on the expression of several heat shock proteins, many of which are expressed in astrocytes. We discovered age-related changes in multiple heat shock proteins in the substantia nigra, caudoputamen, and olfactory bulb, three regions known to develop Lewy pathology in Parkinson's disease. In conclusion, astrocytes can be protected against protein-misfolding stress by upregulation of endogenous glutathione defenses or by N-acetyl cysteine treatment. Furthermore, some heat shock proteins are increased with aging, perhaps as an endogenous defense against proteotoxic stress in older animals.

Format

PDF

Language

English

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