Apoptotic factors and mitochondrial complexes assist determination of strain-specific susceptibility of mice to Parkinsonian neurotoxin MPTP

Abstract

Identification of genetic mutations in Parkinsons disease (PD) promulgates the genetic nature of disease susceptibility. Resilience-associated genes being unknown till date, the normal genetic makeup of an individual may be determinative too. Our earlier studies comparing the substantia nigra (SN) and striatum of C57BL/6J, CD-1 mice and their F1-crossbreds demonstrated neuroprotective role of admixing, against the neurotoxin MPTP. Further, the differences in levels of mitochondrial fission/fusion proteins in the SN of parent strains, imply effect on mitochondrial biogenesis. Our present investigations suggest that the baseline levels of apoptotic factors Bcl-2, Bax and AIF differ across the three strains and, are differentially altered in SN following MPTP-administration. The reduction in complex-I levels exclusively in MPTP-injected C57BL/6J, reiterate mitochondrial involvement in PD pathogenesis. The MPTP-induced increase in complex-IV, in the nigra of both parent strains may be compensatory in nature. Ultrastructural evaluation showed fairly preserved mitochondria in the dopaminergic neurons of CD-1 and F1-crossbreds. However, in CD-1, the endoplasmic reticulum demonstrated distinct luminal enlargement, bordering onto ballooning, suggesting proteinopathy as a possible initial trigger. The increase in -synuclein in the pars reticulata of crossbreds suggests a supportive role for this output nucleus in compensating for the lost function of pars compacta. Alternatively, since -synuclein over-expression occurs in different brain regions in PD, the -synuclein increase here may suggest similar pathogenic outcome. Further understanding is required to resolve this biological contraption. Nevertheless, admixing reduces the risk to MPTP by favouring anti-apoptotic consequences. Similar neuroprotection may be envisaged in the admixed populace of Anglo-Indians.