Date Approved

12-2017

Document Type

Dissertation

Degree Name

PhD in Cell & Molecular Biology

Department

Cell Biology and Neuroscience

College

Graduate School of Biomedical Sciences

First Advisor

Jeremy Francis, PhD

Committee Member 1

Paola Leone, PhD

Committee Member 2

Robert Nagele, PhD

Committee Member 3

Renee Demarest, PhD

Committee Member 4

Michael Law, PhD

Subject(s)

N-acetylaspartate; Neurodegenerative Diseases; aspartoacylase; Oligodendroglia; Neurons; Brain

Disciplines

Cell and Developmental Biology | Cell Biology | Laboratory and Basic Science Research | Life Sciences | Medicine and Health Sciences | Molecular and Cellular Neuroscience | Molecular Biology | Nervous System Diseases

Abstract

N-acetylaspartate (NAA) is a non-invasive clinical marker of neuronal metabolic integrity because of its strong proton magnetic resonance spectroscopy (H-MRS) peak and direct correlation with energetic integrity. Specifically, NAA is used to track the progression of neurodegenerative diseases due to the characteristic reduction of whole brain levels of NAA which occur simultaneously with reduced glucose utilization and mitochondrial dysfunction, but prior to the onset of disease specific pathology. However, NAA will also significantly increase simultaneously with energetic integrity during periods of recovery or remission in applicable disorders, such as traumatic brain injuries. Unfortunately, it remains enigmatic exactly why NAA is so tightly linked to overall neuronal integrity and why its levels seem to decrease prior to disease pathology. In order to shed some light on this unknown, we undertook an analysis of NAA metabolism in two distinct contexts, neurodegenerative disease progression and post-natal development.

We first analyzed possible controlling mechanisms behind the characteristic drop in whole brain levels of NAA during neurodegenerative disease progression using the 5xFAD mouse model of Familial Alzheimer's Disease. During 5XFAD disease progression, the reduction of NAA could not be accounted for by neuronal loss, mitochondrial loss, or the reduction of substrate-providing mechanisms. However, our results revealed that Nat8L, the gene encoding the NAA synthetic enzyme, was significantly down-regulated simultaneously with reduced levels of NAA as well as reduced mitochondrial integrity. We also show that both reductions are preceded by a significant up-regulation of the gene encoding oligodendrocytic aspartoacylase (ASPA); the sole known NAA-catabolizing enzyme. Therefore, we hypothesized that NAA is reduced during 5XFAD progression due the active down-regulation of Nat8L and up-regulation of ASPA in response to reduced energetic integrity.

We then analyzed the expression of Nat8L during the first 4-weeks of postnatal development of ASPA null (Nur7) mice. Our results revealed that Nat8l was up-regulated during a period of early postnatal development normally punctuated by low Nat8L expression and the transcriptional up-regulation of ASPA. Taken together, the results from our 5XFAD and Nur7 experiments indicate ASPA as a possible negative regulator of Nat8L in response to energetic crisis. The results also predict the presence of signaling mechanisms involving cross talk between neurons and oligodendrocytes which control NAA metabolism during both postnatal development and neurodegenerative disease progression.

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