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Admixing of MPTP-Resistant and Susceptible Mice Strains Augments Nigrostriatal Neuronal Correlates to Resist MPTP-Induced Neurodegeneration

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Abstract

Disease genetics in admixed populations like Hispanic-Americans, African-Americans, etc. are gaining importance due to high disease burden in them. Furthermore, epidemiological studies conclusively prove ethnicity-based differential prevalence of Parkinson’s disease (PD), since the American-Caucasians are more susceptible than Asian-Indians and Africans. Contradictorily, Anglo-Indians, an admixture of Europeans and Asian-Indians are five-times less susceptible than Indians. We evaluated the neural basis of this phenomenon using the cytomorphological features of susceptibility to nigrostriatal neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The nigral dopaminergic neuronal numbers, their size and tyrosine hydroxylase (TH), PitX3 and Nurr1 expression were compared in MPTP-susceptible C57BL/6J mice, MPTP-resistant CD-1 mice and their crossbreds using stereology, morphometry and densitometry. Apoptotic index was evaluated by TUNEL-assay and caspase-3 expression. Striatal volume, TH and glial derived neurotrophic factor (GDNF) expression were studied. The normal CD-1 and crossbreds had significantly more, although smaller, nigral dopaminergic neurons than C57BL/6J, and a larger striatum. The crossbreds had higher TH, Nurr1 and PitX3 levels. MPTP administration caused loss of ~50–60 % nigral dopaminergic neurons in C57BL/6J and ~15 % in CD-1, but none in crossbreds. MPTP-induced cellular shrinkage in C57BL/6J was contrasted by nuclear enlargement without somal alterations in resistant strains. MPTP lowered the striatal TH and GDNF in C57BL/6J. Elevated striatal GDNF in CD-1 and crossbreds could be of compensatory nature and complemented the reduced nigral caspase-3 expression to attenuate and/or block apoptosis. Similar neural correlates of resilience are envisaged in the Anglo-Indian population. Thus, we present the core neuroanatomical features of resilience against PD and evidence for ethnicity-based differential prevalence.

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Acknowledgments

The study was funded by the Science and Engineering Research Board, Department of Science and Technology, Govt. of India to PAA (Project no. SR/SO/HS-0121/2012). VDJ is a NIMHANS fellow; HY is a UGC fellow. The authors are grateful to Dr. Bindu M. Kutty, Prof. and Head, Dept. of Neurophysiology, NIMHANS for extending laboratory facilities, Dr. G.H. Mohan, Head Veterinarian at National Centre for Biological Sciences, Bengaluru for providing breeding colonies of CD-1 mice strain, Mr. Niranjan S. for standardizing immunoblots and Ms. Vaidehi Kelkar for densitometric quantification of few striatal samples.

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Vidyadhara, D.J., Yarreiphang, H., Raju, T.R. et al. Admixing of MPTP-Resistant and Susceptible Mice Strains Augments Nigrostriatal Neuronal Correlates to Resist MPTP-Induced Neurodegeneration. Mol Neurobiol 54, 6148–6162 (2017). https://doi.org/10.1007/s12035-016-0158-y

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