Gene

Kinase

Activating transcription factor

Mitogen-activated protein kinase kinase

Cell biology

Amyotrophic lateral sclerosis

Proteostasis

Biology

Neurodegeneration

XBP1

Biochemistry

Endoplasmic reticulum

Protein kinase A

ATF6

Unfolded protein response

EIF-2 kinase

Cyclin-dependent kinase 2

RNA splicing

Endoplasmic-reticulum-associated protein degradation

Internal medicine

Protein kinase R

Medicine

Disease

International Journal of Molecular Sciences

The endoplasmic reticulum (ER) is an important organelle involved in protein quality control and cellular homeostasis. The accumulation of unfolded proteins leads to an ER stress, followed by an adaptive response via the activation of the unfolded protein response (UPR), PKR-like ER kinase (PERK), inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) and activating transcription factor 6 (ATF6) pathways. However, prolonged cell stress activates apoptosis signaling leading to cell death. Neuronal cells are particularly sensitive to protein misfolding, consequently ER and UPR dysfunctions were found to be involved in many neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and prions diseases, among others characterized by the accumulation and aggregation of misfolded proteins. Pharmacological UPR modulation in affected tissues may contribute to the treatment and prevention of neurodegeneration. The association between ER stress, UPR and neuropathology is well established. In this review, we provide up-to-date evidence of UPR activation in neurodegenerative disorders followed by therapeutic strategies targeting the UPR and ameliorating the toxic effects of protein unfolding and aggregation.

Endoplasmic Reticulum Stress and Unfolded Protein Response in Neurodegenerative Diseases