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

Huntington's disease is a progressive and fatal neurodegenerative disease, and the mechanism that causes neuronal apoptosis has not been fully elucidated [61]. Studies have shown that ER stress, which occurs as a result of misfolded protein accumulation, which may contribute to neuronal loss, may play a role [62]. Although different studies have shown a role for the UPR in HD, the evidence is inconclusive [63]. In a study, RAB5A, HMGB1, CTNNB1, DNM1, TUBB, TSG101, EEF2, DYNC1H1, SLC12A5, ATG5, AKT1, CASP7, and SYVN1 genes were identified, which would suggest a potential link between UPR and Huntington's disease [64, 65]. A significant association was found in the length of the polyglutamine pathway of Huntington, which is a critical determinant of disease onset in human HD patients and points to the UPR as a promising target for therapeutic intervention [66].

The most affected region in terms of histopathological changes in HD is the striatal region. However, it was determined that gray and white matter were affected in cortical and noncortical areas. In addition, aggregates/inclusions are characteristic histopathological markers of HD.

#### **7. Conclusion**

As a result, the accumulation of unfolded or misfolded proteins in the cytosol under ER stress is an important mechanism in the occurrence of cell damage. PERK IRE1, and ATF6, which sense this protein folding response, play an important role in shaping the cellular pathway. In addition, the relationship between ER stress and mitochondria is important in the maintenance of cellular response. ER stress plays

an important role in the pathogenesis of many neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington's. Knowing the histopathological changes seen in these diseases is very important in the diagnosis of the disease. The role of misfolded or unfolded protein response in ER stress in neurodegenerative diseases, and the histopathological changes in these diseases will help to develop therapeutics for neurodegenerative diseases.
