PerspectiveModulation of endoplasmic reticulum stress in Parkinson's disease
Section snippets
Parkinson's disease and treatment
Parkinson's disease is a neurodegenerative disease characterized by three major symptoms: akinesia, rigidity, and tremors (Savitt et al., 2006). In patients with Parkinson's disease, there is a reduction in the number of dopaminergic neurons in the substantia nigra, a region of the midbrain. Additionally, the high acetylcholine activity caused by dopamine deficiency results in dyskinesia (Zhou et al., 2008). However, the mechanisms underlying the reduction in dopaminergic neurons remain unclear
ER stress and disease
The ER controls the quality of proteins, and contributes to the maintenance of the normal protein function by modulating intracellular calcium levels and the folding of proteins that are synthesized within the cells (Kwang Soo, 1965). Unfolded proteins induce ER stress by accumulating in the ER, and activating molecules such as activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1), and protein kinase RNA-like endoplasmic reticulum kinase (PERK), which are the major ER
ER stress response in Parkinson's disease
Many reports suggest the involvement of ER stress in the pathology of Parkinson's disease. For instance, the activity of ATF6 is inhibited by α-synuclein, which characteristically aggregates in the Parkinson’s disease state (Credle et al., 2015). α-synuclein aggregation by nutrient deprivation commences following the ER stress response (Jiang et al., 2014), silencing the UPR transcription factors such as x-box binding protein 1 (XBP-1), and triggers chronic ER stress and dopaminergic neuron
Effect of zonisamide against ER stress
Zonisamide has been used as an anti-epileptic drug at high doses of 200–400 mg/day. It was originally defined as a T-type calcium channel inhibitor and a sodium channel blocker (Suzuki et al., 1992). However, it has been revealed that zonisamide yields a therapeutic effect in Parkinson's disease at a low dose of 25 mg/day (Murata et al., 2001). Zonisamide works by inhibiting monoamine oxidase-B activity and boosting tyrosine hydroxylase activity. In addition, it has been revealed that zonisamide
General conclusion and future perspective
These findings indicate that ER stress may play a role in neurodegeneration in Parkinson's disease, and that zonisamide is neuroprotective against ER stress via caspase-3 inhibition. On the other hand, effective neuroprotective agents are not currently available for the treatment of Parkinson's disease. It is possible that therapeutic agents for Parkinson's disease, such as zonisamide, could be developed in the future by targeting the factors involved in ER stress, or those downstream of this
Acknowledgements
We received a financial support of Dainippon Sumitomo Pharma Co., Ltd. (Osaka, Japan) as a collaborative research, and the present study was conducted by using zonisamide and its constituents of the company.
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2018, Biochemical and Biophysical Research CommunicationsCitation Excerpt :However, it has not been clarified if oxicam-NSAIDs suppressed ER stress response and mitochondrial dysfunction. Since ER stress is a causative mechanism underlying nigrostriatal degeneration in PD [22,23], we investigated if oxicam-NSAIDs would affect ER stress-related genes. First, we confirmed that oxicam-NSAIDs suppressed cell death and activation of caspase-3 induced by MPP+, and found that oxicam-NSAIDs partially suppressed cell death and activation of caspase-3 caused by tunicamycin (ER stress-inducer).