title: Admixing of MPTP-Resistant and Susceptible Mice Strains Augments Nigrostriatal Neuronal Correlates to Resist MPTP-Induced Neurodegeneration.
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.
authors.affiliation: Department of Neurophysiology, National Institute of Mental Health and Neurosciences, Hosur Road, Bengaluru, -560029, India.
authors.forename: D J
authors.initials: DJ
authors.lastname: Vidyadhara
authors.affiliation: Department of Neurophysiology, National Institute of Mental Health and Neurosciences, Hosur Road, Bengaluru, -560029, India.
authors.forename: H
authors.initials: H
authors.lastname: Yarreiphang
authors.affiliation: Department of Neurophysiology, National Institute of Mental Health and Neurosciences, Hosur Road, Bengaluru, -560029, India.
authors.forename: T R
authors.initials: TR
authors.lastname: Raju
authors.affiliation: Department of Neurophysiology, National Institute of Mental Health and Neurosciences, Hosur Road, Bengaluru, -560029, India. alladiphalguni@gmail.com.
authors.forename: Phalguni Anand
authors.initials: PA
authors.lastname: Alladi
mesh_terms: D000818:Animals; D002452:Cell Count; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020267:MPTP Poisoning / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D014446:Tyrosine 3-Monooxygenase
keywords: Dopaminergic neurons; Dorsal striatum; First filial generation crossbreds; MPTP susceptibility; Parkinson’s disease prevalence; Substantia nigra pars compacta