Lipid Metabolism and Proteostasis Interdependencies and Implications for Nuclear Envelope Dysfunction and Neurodegenerative Disease

The maintenance of cellular homeostasis features the interplay between the mechanisms of proteostasis and lipid metabolism with the integrity of the nuclear envelope (NE). When disruptions to this balance occur, cells become more susceptible to the pathogenesis of diseases that involve ER stress or neurodegeneration, such as nonalcoholic fatty liver disease (NAFLD) and Alzheimer's disease (AD). Focusing on the impact of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling, this review analyzes the molecular mechanisms that support the interconnected pathways of lipid metabolism and proteostasis: AMP-activated protein kinase (AMPK) and Stearoyl-CoA Desaturase 1 (SCD1) are two examples of molecular targets to preserve NE integrity and mitigate proteotoxic stress. Examination of these mechanisms can lead to the development of treatments—potentially involving small molecules and gene therapies—to restore lipid and proteostasis balance. By comprehending the interdependency between proteostasis and lipid metabolism, we can develop a new understanding of the complex cellular pathways involved with the ER and NE to develop therapeutics to address diseases associated with the dysfunction of these organelles.