Date of Award

2020

Embargo Period

5-27-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell and Molecular Pharmacology and Experimental Therapeutics

College

College of Graduate Studies

First Advisor

Marcelo Vargas

Second Advisor

Joe Blumer

Third Advisor

Sherine Chan

Fourth Advisor

Richard Drake

Fifth Advisor

Stephen Tomlinson

Abstract

Most physiological processes in mammals are subjected to daily oscillations governed by a circadian system. Circadian rhythm orchestrates metabolic pathways in a time-dependent manner and loss of circadian timekeeping has been associated with cellular and system-wide alterations in metabolism, redox homeostasis, and inflammation. Nuclear Receptor subfamily 1 group D member 1 (NR1D1) is a transcription factor that participates in the molecular clock that encodes circadian rhythms and links metabolism and inflammation to circadian cycles. Fatty acid binding protein 7 (FABP7), an NR1D1 target, is a regulator of lipid metabolism, energy homeostasis, and inflammation. FABP7 can regulate fatty acid uptake, transport, and availability to nuclear receptors. In the adult brain, FABP7 is especially abundant in astrocytes that haven cytoplasmic granules originated from damaged mitochondria. Mitochondrial dysfunction and altered metabolism have been implicated in amyotrophic lateral sclerosis (ALS), either as a primary cause or as a secondary component of the pathogenic process. We investigated clock and clock-controlled genes in multiple tissues from transgenic mice expressing a mutant superoxide dismutase 1(SOD1)-linked to ALS. We identified tissue-specific changes in the relative expression as well as altered daily expression patterns of clock genes, sirtuins, metabolic enzymes, and redox regulators. We discovered NR1D1 is downregulated and FABP7 is upregulated in the spinal cord of symptomatic mutant hSOD1-expressing mice. Decreasing NR1D1 or increasing FABP7expression in primary non-transgenic astrocytes resulted in a pro-inflammatory profile and decreased neuronal survival when co-cultured with motor neurons. Moreover, astrocytes isolated from symptomatic hSOD1-expressing mice displayed endogenous up-regulation of FABP7 and silencing of FABP7 in these cultures decreased inflammatory markers and toxicity towards co-cultured motor neurons. At an organism level, our results suggest the possibility of disrupted peripheral clock synchronization in hSOD1G93A mice, while at a cellular level we demonstrate that NR1D1 and FABP7 markedly alter the biology of astrocytes and the way these cells interact with neurons. Since metabolism and redox homeostasis are intimately entangled with circadian rhythms, our data suggest that altered expression of clock genes may contribute to metabolic and redox impairment in ALS and we identify NR1D1 and FABP7 as potential therapeutic targets to prevent astrocyte-mediated motor neuron toxicity in ALS.

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All rights reserved. Copyright is held by the author.

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