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Apoptotic Factors and Mitochondrial Complexes Assist Determination of Strain-Specific Susceptibility of Mice to Parkinsonian Neurotoxin MPTP

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Abstract

Identification of genetic mutations in Parkinson’s 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 the neuroprotective role of admixing against the neurotoxin MPTP. Furthermore, the differences in levels of mitochondrial fission/fusion proteins in the SN of parent strains imply effects 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 reiterates mitochondrial involvement in PD pathogenesis. The MPTP-induced increase in complex-IV, in the nigra of both parent strains, may be compensatory in nature. The 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 α-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 α-synuclein over-expression occurs in different brain regions in PD, the α-synuclein increase here may suggest a similar pathogenic outcome. Further understanding is required to resolve this biological contraption. Nevertheless, admixing reduces the risk to MPTP by favoring anti-apoptotic consequences. Similar neuroprotection may be envisaged in the admixed populace of Anglo-Indians.

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Acknowledgements

The authors are grateful to Dr. G.H. Mohan, Head Veterinarian at the National Centre for Biological Sciences, Bengaluru, for providing breeding colonies of CD-1 mice strain. We are grateful to Dr. Abhilash PL for his help in sampling the fecal microbiome.

Availability of Data and Materials

The datasets generated during and/or analyzed during the current study are not publicly available since these observations are yet not published, but will be available from the corresponding author on reasonable request.

Funding

The study was funded by the Science and Engineering Research Board, Department of Science and Technology, Govt. of India to PAA (No. SR/SO/HS-0121/2012). HY was a University Grants Commission (UGC) fellow HY received (1) IBRO travel grant to present a part of the study at IBRO/APRC School Panjab University, 2015 and (2) Department of Biotechnology India Travel grant, to present a part of this study at 5th Asian & Oceanian Parkinson’s Disease and Movement Disorders Congress, Manila, 2016. VDJ was a NIMHANS fellow. The infrastructural support was provided by NIMHANS.

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Authors and Affiliations

  1. Department of Neurophysiology, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore, India

    Haorei Yarreiphang, D J Vidyadhara, Anand Krishnan Nambisan, Trichur R Raju & Phalguni Anand Alladi

  2. Present address: Zoology Department, Hansraj College, University of Delhi, Delhi, 110007, India

    Haorei Yarreiphang

  3. Present address: Departments of Neurology and Neuroscience, Yale University School of Medicine, New Haven, CT, USA

    D J Vidyadhara

  4. Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, 560029, India

    BK Chandrashekar Sagar

  5. Department of Clinical Psychopharmacology and Neurotoxicology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, 560029, India

    Phalguni Anand Alladi

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  1. Haorei Yarreiphang
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  2. D J Vidyadhara
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Contributions

Phalguni Anand Alladi (PAA) and Haorei Yarreiphang (HY) contributed to the study conception and design. Material preparation, data collection, and analysis were performed by HY, D J Vidyadhara, Anand Krishnan Nambisan, BK Chandrasekar Sagar, and PAA. The first draft of the manuscript was written by HY and reviewed by Trichur R. Raju. All authors commented on previous versions of the manuscript. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Phalguni Anand Alladi.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of our institution which adhere to the CPCSEA and NIH guidelines.

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Not applicable. No human data is being presented in this study.

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Not applicable. No human data is being presented in this study.

Competing Interests

TRR and BKCS were employees of NIMHANS when the study was conducted and have since superannuated. PAA is currently an employee of NIMHANS. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

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Yarreiphang, H., Vidyadhara, D.J., Nambisan, A.K. et al. Apoptotic Factors and Mitochondrial Complexes Assist Determination of Strain-Specific Susceptibility of Mice to Parkinsonian Neurotoxin MPTP. Mol Neurobiol 60, 4778–4794 (2023). https://doi.org/10.1007/s12035-023-03372-1

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