Glucose-6-phosphate dehydrogenase deficiency: A possible risk factor for neurodegeneration associated with aging and amphetamine use
Year: 2013
Type: dissertation
Abstract: Glucose-6-phosphate dehydrogenase (G6PD) regenerates the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), which is important for reactive oxygen species (ROS) detoxification. ROS have been implicated in the development of neurodegenerative diseases in aging as well as the neurotoxic effects of amphetamine analogs. Using a mutant G6PD-deficient mouse model, we investigated the potential neuroprotective role of G6PD in aging-related and amphetamine-initiated neurotoxicity. Aging G6PD-deficient mice exhibited increased DNA damage along with neurodegenerative changes including a marked loss of Purkinje cells. Locomotor deficits linked to cerebellar function were observed in aging G6PD-deficient mice, but no cognitive deficits were detected. Electrophysiological measurements in hippocampal slices showed substantial amplifications of synaptic function in aging G6PD-deficient animals. Conversely, lifespan was increased in aging homozygous G6PD-deficient mice compared to heterozygous G6PD-deficient mice and wild-type G6PD-normal mice. The potential protective role of G6PD against ROS-initiating neurotoxins was examined using 3,4-methylenedioxyamphetamine (MDA), the major active metabolite of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy). Although MDA caused deficits in motor function linked to the substantia nigra, and in cognition measured by taste aversion learning, these deficits were not exacerbated in G6PD-deficient mice, and homozygous G6PD-deficient females were actually protected from one gender-specific MDA-initiated learning deficit observed in wild-type animals. My results show a complex role for G6PD. On one hand, G6PD protected against the neurodegenerative effects of oxidative stress in aging mice at the macromolecular, cellular and behavioural levels while the substantial electrophysiological alterations in G6PD-deficient mice suggest that cognitive deficits remain to be discovered. In contrast, the enhanced lifespan of G6PD-deficient mice suggests that a reduction of products from the pentose phosphate pathway including NADPH may have benefits, which mechanisms also remain to be examined. The absence of a modulatory role for G6PD in some learning deficits caused by MDA in adult mice suggests limitations in the protective ability of G6PD, while the reduction in another MDA-initiated behavioural deficit in G6PD-deficient females reveals the same paradoxical potential seen in aging mice. While G6PD appears to exert a predominantly neuroprotective role, particularly in aging, the beneficial outcomes from G6PD deficiency may be relevant to the high prevalence of it in humans.
Source: TSpace (University of Toronto)
Author: Margaret M. Loniewska
Language: English
Subfield: Aging
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2537468432