Author ORCID Identifier
Date of Graduation
Doctor of Philosophy (PhD)
Louise D. McCullough
M. Neal Waxham
Andrew J. Bean
Peroxisomes are small organelles with critical functions: lipid synthesis, breakdown of reactive oxygen species by antioxidant enzymes, and amino acid degradation. In the brain, peroxisomal lipids make up the myelin sheath. Brain peroxisomal dysfunction leads to lipid disruption or neurological consequences if key peroxisomal proteins are absent. Still, it is unclear how peroxisomes are affected in neurodegenerative diseases and in normal brain aging. This work examines peroxisomal markers in three settings: 1) in a neuronal and 2) animal model of Huntington disease (HD), where mutant huntingtin (mHtt), the causative protein in Huntington disease pathogenesis is expressed, and 3) in the cortices of aged mouse brains.
First, we found that the rate of peroxisomes being moved to acidic lysosomes increased in a neuronal HD model compared to control neurons, indicating that mHtt expression amplified the peroxisomal degradation process. We also found that in the cortices of a presymptomatic HD mouse model, neuronal levels of PEX5, (a peroxisomal protein involved in clearance and homeostasis of peroxisomes) and ACAA1 (a peroxisomal marker), were lower than in control groups, suggesting that before HD symptoms begin, mHtt expression may reduce peroxisomal number in neurons, and affect peroxisomal homeostasis by reducing PEX5 levels. These changes, while unexpected, had us wondering if brain aging affected PEX5 levels, since metabolic pathways become impaired as the brain ages.
Secondly, we investigated how age and sex affect cortical PEX5 levels of aged male and female mice. We discovered that PEX5 is lower in aged male brains than in young male brains, lower Pex5 cortical expression in aged males compared to younger males, and lower neuronal PEX5 levels in aged male and female cortices, compared to young male and female cortices. In conclusion, aging has a negative effect on neuronal PEX5 levels in aging mouse brains of both sexes.
This novel work investigates how PEX5 levels are affected in models of a neurodegenerative disease and in the typical aged mouse brain, setting a foundation for further investigation of the role of peroxisomal proteins in the progression of normal neuronal aging and neurodegenerative disease.
PEX5, pexophagy, neuronal peroxisomes, peroxisomal protein, brain peroxisomes, aging brain