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Dopamine and its metabolites in cathepsin D heterozygous mice before and after MPTP administration
Donna Crabtree1, Michaël Boyer-Guittaut, Xiaosen Ouyang
1Department of Pathology, University of Alabama at Birmingham, AL 35294, USA.
Abstract:
Cathepsin D (CD) is a lysosomal aspartyl protease which plays an important role in α-synuclein degradation, and neuronal survival. CD knockout mice die by post-natal day 25±1 due to intestinal necrosis. We analyzed the young adult male heterozygous mice, and found no behavior abnormalities in the heterozygous mice compared to wildtype littermates. LC3-II, p62, and α-synuclein levels are similar, while LAMP1 is higher in the striatum in CD heterozygous compared to wildtype mice. Interestingly, we found that dopamine and metabolites in the striatum and olfactory bulbs are at higher levels than wildtype littermates, while the DOPAC/DA and HVA/DA ratio remain similar between wildtype and CD heterozygous mice. In response to sub-chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, dopamine, DOPAC, and HVA are depleted to similar levels in the striatum in both heterozygous and wildtype mice. Dopamine synthesizing enzyme tyrosine hydroxylase, metabolic enzyme monoamine oxidase, and catechol-O-methyltransferase (COMT) levels are similar in the striatum in wildtype and heterozygous mice. These studies provide valuable information regarding how lysosomal function may contribute to neurochemical homeostasis in animal models.
Insights
Cathepsin D (CD) deficiency in mice alters dopamine levels without affecting behavior or response to MPTP. This suggests lysosomal function impacts neurochemical balance.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Cathepsin D (CD) is a lysosomal protease crucial for α-synuclein degradation and neuronal survival.
- CD knockout mice exhibit early mortality due to intestinal necrosis.
Purpose of the Study:
- To investigate the neurochemical and behavioral impact of heterozygous Cathepsin D deficiency.
- To assess the role of lysosomal function in maintaining neurochemical homeostasis.
Main Methods:
- Analysis of young adult male heterozygous CD mice and wildtype littermates.
- Behavioral testing, Western blotting for protein levels (LC3-II, p62, α-synuclein, LAMP1), and measurement of dopamine and its metabolites.
- MPTP administration to assess response to neurotoxin-induced dopamine depletion.
Main Results:
- Heterozygous CD mice showed no behavioral abnormalities.
- Increased LAMP1 levels in the striatum, with higher dopamine and metabolite levels in striatum and olfactory bulbs.
- Similar depletion of dopamine and metabolites after MPTP administration in both groups.
- Unchanged levels of dopamine-synthesizing and metabolizing enzymes.
Conclusions:
- Partial Cathepsin D deficiency leads to altered dopamine homeostasis without affecting behavior or neurotoxin response.
- Lysosomal function, specifically Cathepsin D, plays a role in regulating dopamine levels in the brain.
- These findings contribute to understanding the link between lysosomal dysfunction and neurochemical balance.
