Cardinal role of eukaryotic initiation factor 2 (eIF2α) in neuronal
death : implication of PERK:IRE1α:ATF6 axis in Parkinson’s pathology
Abstract
Background and purpose - In spite of decades research the etiology of
Parkinson’s disease (PD) is not yet well defined. The present study was
conducted to assess the role of eukaryotic initiation factor 2 (eIF2α)
in progressive dopaminergic neuronal death. Experimental approach - The
investigation was done employing experimental rat model of parkinsonism
and utilizing various interventions (YM08, 4µ8C, AEBSF, salubrinal,
ursolic acid) of endoplasmic reticulum (ER) stress signaling. The mRNA
and protein level of ER stress related signaling factors (GRP78, IRE1α,
ATF6, eIF2α, ATF4, XBP-1, GADD153) were estimated along with various
biochemical alterations (reactive oxygen species generation, levels of
nitrite level, intracellular calcium, mitochondrial membrane potential),
neuronal morphology and neuronal apoptosis after 3 and 7 day of
experiment initiation. Key results - Findings with single administration
of interventions showed that salubrinal exhibited significant protection
against rotenone induced alterations in ER stress related signaling
factors in comparison to other interventions. Therefore, further study
was expanded with repeat dose of salubrinal. Rotenone administration in
rat brain caused the dose dependent progressive neuronal death which was
significantly attenuated with salubrinal treatment involving its diverse
effects on altered levels of various ER stress related signaling factors
and altered biochemical parameters. Conclusion and implications -
Findings showed that rotenone administration induced PD pathology
involve the dose dependent progressive neuronal death including various
biochemical alterations with critical role of eukaryotic initiation
factor 2α, suggesting the potential pharmacological utilization of
salubrinal or salubrinal like molecule in therapeutics of Parkinson’s
diseases.