Dissertation/Thesis Abstract

Deficient aldehyde detoxification in the nigrostriatal pathway: A potential animal model for Parkinson's disease
by Wey, Margaret Chia-Ying, Ph.D., The University of Texas Health Science Center at San Antonio, 2012, 137; 3509120
Abstract (Summary)

Parkinson's disease (PD) is the 2nd most common neurodegenerative disorder after Alzheimer's disease, affecting 2 – 5 % of individuals over the age of 65 – 85. PD is characterized by progressive deficits in motor function resulting primarily from neuronal degeneration in the nigrostriatal pathway. Numerous studies have indicated that accumulation of oxidative insults and misfolded proteins during aging contribute to disease pathogenesis (Schapira et al., 1990, Adams et al., 2001, Jenner, 2003, McNaught and Olanow, 2003, 2006, Schulz, 2008). The most destructive sources of oxidative stress are biogenic aldehydes.

Biogenic aldehydes are particularly toxic due to their relatively long half-life and the fact that they can easily cross cell membranes, acting as second toxic messengers (Marchitti et al., 2007). Biogenic aldehydes arise from various physiological processes, including biotransformation of neurotransmitters and lipids. For example, dopamine gives rise to 3,4-dihydroxyphenylacetaldehyde (DOPAL), and lipid peroxidation generates 4-hydroxynonenal (4-HNE), acrolein and malondialdehyde (MDA). Elevated levels of biogenic aldehydes have been reported in the post-mortem brains of patients with PD (Yoritaka et al., 1996, Castellani et al., 2002, Jenner, 2003, Goldstein et al., 2010). Aldehyde dehydrogenase (ALDH) is the primary mechanism for aldehyde detoxification in the brain (Pettersson and Tottmar, 1982, Choudhary et al., 2005). ALDH1A1 and ALDH2 are the two isoforms known to be expressed in dopaminergic neurons (Vasiliou and Nebert, 2005, Westerlund et al., 2005, Alnouti and Klaassen, 2008). ALDH2 deficiency has been implicated as a risk factor in Alzheimer's disease (AD) which, like PD, is a neurodegenerative and protein aggregation disorder (Wang et al., 2008, Michel et al., 2010). Moreover, reduced ALDH1A1 gene expression has been reported in the substantia nigra and other tissues in PD (Galter et al., 2003, Grunblatt et al., 2004, Mandel et al., 2005). In addition, impaired mitochondrial complex I activity, which is well documented in PD, reduces the availability of the NAD+ co-factor required by multiple ALDH isoforms to catalyze the removal of biogenic aldehydes.

The presence of insoluble cytosolic protein aggregates, known as Lewy bodies (LB), in the brain is a pathological hallmark of PD. The major constituents of LB are &agr;-synuclein and ubiquitin (Spillantini et al., 1997, Spillantini et al., 1998). Natively unfolded &agr;-synuclein can form aggregates and impede cell survival. It was reported that increased oxidative stress, including aldehydes, facilitated &agr;-synuclein oligomerization and aggregation (Galvin, 2006, Qin et al., 2007, Shamoto-Nagai et al., 2007a, Lee et al., 2009). However, it had not been established whether the accumulation of biogenic aldehydes plays a causal role in PD pathogenesis or if ALDH1A1 and ALDH2 deficiency increases the risk of PD development. We hypothesize that elevated biogenic aldehydes resulting from impaired aldehyde detoxification results in behavioral deficits, neurochemical changes and neuropathological manifestations that are characteristic of PD. Furthermore, by enhancing the removal of biogenic aldehydes, the behavioral and pathological manifestations of PD may be ameliorated.

To test this hypothesis, we generated mice that are null for Aldh1a1 and Aldh2 (Chapter II). We then characterized the role of aldehyde detoxification on motor function (Chapter III) as well as neurochemical and neuropathological manifestations of PD (Chapter IV). After establishing a reproducible animal model of impaired aldehyde detoxification with elevated biogenic aldehydes in the nigrostriatal pathway, we determined the effect of the aldehyde scavenging agent, hydralazine, in Aldh1a1 and Aldh2 double knockout mice (Chapter V). We found that deficiency in Aldh1a1 and Aldh2 led to elevation of DOPAL and 4-HNE. The elevation in these two aldehydes preceded the age-related loss of dopamine and metabolites in the nigrostriatal pathway and loss of dopaminergic neurons in the substantia nigra and progressive age-related deficits in motor performance. Moreover, we found that the aldehyde trapping agent, hydralazine, reduced the level of biogenic aldehydes and ameliorated the deficits in motor function. By completing this series of studies, the following goals have been achieved: (1) Developed a potential animal model for PD research; (2) identified elevated aldehyde as a potential mechanism leading to dopaminergic dysfunction in PD; and (3) identified aldehyde scavenging as a potential new therapeutic approach for the treatment of PD.

Indexing (document details)
Advisor: Strong, Randy
Commitee: Chesselet, Marie Francoise, Giuffrida, Andrea, Roberts, James, Strong, Randy, Van Remmen, Holly
School: The University of Texas Health Science Center at San Antonio
Department: Pharmacology
School Location: United States -- Texas
Source: DAI-B 73/09(E), Dissertation Abstracts International
Subjects: Neurosciences, Pharmacology, Aging
Keywords: Aldehyde dehydrogenase, Motor dysfunction, Oxidative stress, Parkinson's disease
Publication Number: 3509120
ISBN: 978-1-267-35308-5
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