Objective: Compare nigral neurons in C57BL/6J, CD-1 and their F1 crossbreds with respect to developmental apoptosis in the nigra during postnatal and to assess MPTP-induced degeneration at adulthood.

Background: Parkinson’s disease has differential prevalence among ethnic groups. Caucasians are more susceptible, Non-whites are less and Admixed populations are better protected. Molecular mechanisms of susceptibility is unknown. Similarly, different mice strains have varying susceptibility to neurotoxin MPTP. Strains with lesser DAergic neurons are more susceptible than those with higher neuron numbers. The differences in the basal nigral neuronal numbers in the adult may be a consequence of differential developmental apoptosis in these mice strains.

Method: Immuno-labelling for pro-, anti-apoptotic proteins, GDNF and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) for apoptotic cells during postnatal development were performed in the susceptible C57BL/6, resistant CD1 and the F1 crossbreds. Electron microscopy, mitochondrial assay, immunolabeling and TUNEL assay were performed in all the adult study groups before and after MPTP administration. Statistical analysis was done by one-way ANOVA and Tukey’s post hoc test.

Results: C57BL/6J is most susceptible and crossbreds least susceptible to MPTP. Large-scale neuronal loss occurred was corroborated by increased apoptosis, pro-apoptotic proteins and a profound ultrastructural damage. The resistant CD1 and crossbreds showed decreased caspase-3, lower Bax:Bcl-2 ratio and enhanced GDNF expression in response to MPTP. Developmental studies observed two peak apoptotic periods (P2 andP14). In the crossbreds, the P14 peak was almost non-existent, C57BL/6J underwent higher magnitude of apoptosis as compared to others. Further, an interesting findings on gut microbiome was the identical composition of Prevotella family in the resistant CD-1 and crossbreds. The microbes of this genus are known to be reduced in human PD patients.

Conclusion: We evaluated mechanisms pertaining to factors associated with the differential susceptibility of C57BL/6J, CD-1 and their crossbreds to MPTP. Evaluation of the postnatal development apoptosis highlighted that the neuronal population size is actually determined during development. The vulnerability to a neurodegenerative disease may arise early during development.

References: 1. Muthane et al., (1994) Experimental Neurology, 126(2), 195–204. 2. Vila, M et al., (2001) Proceedings of the National Academy of Sciences of the United States of America, 98(5), 2837–2842 3. Vidyadhara et al., (2017) Molecular Neurobiology, 54(8), 6148–6162

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MDS Abstracts - https://www.mdsabstracts.org/abstract/evaluation-of-nigral-neuronal-apoptosis-during-postnatal-development-and-adulthood-of-mice-strains-with-differential-sensitivity-to-mptp/