Objective: To evaluate the possible temporal hierarchy of sub-cellular organellar degeneration in experimental models of Parkinson’s disease (PD), using MPTP/MPP⁺

Background: Higher prevalence of PD in Caucasians compared to Asian-Indians and 5-times lower prevalence in Anglo-Indians; the admixed F1-generation of these two ethnicities, is well evinced. On similar lines C57BL/6J, CD-1, and their F1X2 crossbred mice exhibit variable response to the neurotoxin MPTP; where C57BL/6J mice with fewer nigral DA neurons are more vulnerable. Although sub-cellular organellar dysfunction is commonplace during neurodegeneration, rare reports describe the chronology of degeneration of major organelles in response to PD mimetics

Method: Our study traced organellar degeneration in the mice nigro-striatum and SH-SY5Y cell line. The striatum and nigra of control and MPTP-injected C57BL/6J, CD-1 and F1X2 mice (n=5 mice/strain/group) were subjected to immunofluorescence labelling, confocal microscopy-based semi-quantitative analysis, immunoblotting and electron microscopy (EM). For the in-vitro study MPP⁺ exposed SH-SY5Y cells (n=3 cultures in duplicates) were subjected to mitochondria-ER tracker dyes followed by live imaging, mitochondrial respiration analysis and EM in a temporal pattern. Human skin biopsies (n=3-6) were evaluated by EM.

Results: Altered expression of calnexin, TGN-38 as well as ultrastructure hinted that most organelles were severely impaired in the nigro-striatum of C57BL/6J. F1X2 neurons showed mild autophagy induction as seen by LC3 expression. Live cell imaging revealed a gradual loss of ER and mitochondria tags, though initial loss was prominent in ER. The spikes in mitotracker labelling at early time points hint at mitochondrial biogenesis, and was supported by presence of spherical and tubular mitochondria in the cells. In patient skin biopsies, most organelles had abnormal ultrastructure, alongside decompacted myelin and an increase in intermediate filaments.

Conclusion: Mild induction of autophagy and mitochondrial biogenesis may be the coping strategies of neurons. Similarities in C57BL/6J and patient skin suggest parallels in pathogenesis and a reliable replication in the model. The chronology of degeneration of neuronal organelles as seen in SHSY5Y cells may be critical determinants of PD pathogenesis and useful in designing therapeutics.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/sub-cellular-alterations-in-mptp-induced-in-vivo-and-in-vitro-systems-and-non-mptp-human-parkinsonian-skin-biopsies-verifying-the-sequelae-of-differential-toxicity/