Abstract <p>Proteostasis is the process by which cells maintain proteome integrity through interconnected signalling networks that regulate protein synthesis, folding, assembly, transport and degradation. The subcellular organelle endoplasmic reticulum (ER), plays a central role in proteostasis, consisting of vital protein regulating components. ER function is altered as aging proceeds and challenged through many different internal or external signals; which might result in protein misfolding and aggregation of aberrant proteins in the ER lumen. This phenomenon is known as ER stress; stimulating the activation of a survival response called unfolded protein response (UPR). ER dysfunction and proteostasis impairment is implicated in neurodegeneration, developing the basis for various neurodegenerative diseases (NDs) including Alzheimer’ disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS) and more. In that aspect, targeting ER stress and UPR in translational studies is promising hope for the treatment of these diseases from a molecular perspective. Therefore, we aimed to provide a general understanding of proteostasis, ER stress, UPR signalling and how these cellular processes are related to neurodegeneration. We presented insights on the research regarding therapeutic approaches of NDs which intend to target molecular components.</p>