**4. Endoplasmic reticulum (ER) stress response and histopathological changes in Parkinson's disease**

Parkinson's disease is a neuropathological disease involving the degeneration of dopaminergic neurons in the substantia nigra followed by loss of their terminals in the striatum [44]. The main clinical manifestations are resting tremor, bradykinesia, rigidity, and postural reflex dysfunction [44]. Currently, the cause of nigral degeneration, which is responsible for the development of the symptoms of this disease, is unknown. However, considering the studies, it is thought that hereditary predisposition, environmental toxins, and aging play an important role in this process and multifactorial causes come to the fore in etiopathogenesis. Various studies have shown that ER stress plays an essential role in the pathophysiology of Parkinson's [45]. ER stress occurs when protein aggregates and fibril accumulation in the Parkin cell with increased ROS in Parkinson's disease. In a study, it was reported that ER stress occurred in the cell culture medium. In another study, UPR components such as transcriptional factors and CHOP and ER chaperones in neurons cause damage to cells [45, 46]. It has also been stated that IRE, PERK, and ER stress kinase phosphorylation, which are involved in ER stress, play a role in Parkinson's and cause the degeneration of dopaminergic neurons [47]. Again, as a result of some studies, it has been reported that 6-OHDA and MPP+ applied to create experimental Parkinson's show their effects by triggering the UPR increase in neurons.

Characteristic features of Parkinson's disease include loss of neurons in certain areas of the brain region called the substantia nigra and extensive accumulation of intracellular protein (alpha-synuclein) [48]. While the loss of pigmented dopaminergic neurons in the substantia nigra and accumulation of α-synuclein in neurons are not specific for Parkinson's disease, these two major neuropathologies, when observed together, are specific for definitive diagnosis of idiopathic Parkinson's disease [49, 50].
