Introduction ER stress and the UPR ER stress–induced apoptosis ER stress and autophagy The UPR and neurodegenerative disease Future perspectives The stimuli for neuronal cell death in neurodegenerative disorders are multi‐factorial and may include genetic predisposition, environmental factors, cellular stressors such as oxidative stress and free radical production, bioenergy failure, glutamate‐induced excitotoxicity, neuroinflammation, disruption of Ca²⁺‐regulating systems, mitochondrial dysfunction and misfolded protein accumulation. Cellular stress disrupts functioning of the endoplasmic reticulum (ER), a critical organelle for protein quality control, leading to induction of the unfolded protein response (UPR). ER stress may contribute to neurodegeneration in a range of neurodegenerative disorders. This review summarizes the molecular events occurring during ER stress and the unfolded protein response and it specifically evaluates the evidence suggesting the ER stress response plays a role in neurodegenerative disorders.

Introduction Mitochondria and cell death Mitochondrial outer membrane permeabilization (MOMP): point of no return Mitochondrial IMS: poison cabinet Mitochondrial pathway of cell death and disease pathogenesis Therapeutic strategies that promote MOMP and cell death Therapeutic strategies that inhibit MOMP and cell death Conclusion and future directions The mitochondrial pathway to apoptosis is a major pathway of physiological cell death in vertebrates. The mitochondrial cell death pathway commences when apoptogenic molecules present between the outer and inner mitochondrial membranes are released into the cytosol by mitochondrial outer membrane permeabilization (MOMP). BCL‐2 family members are the sentinels of MOMP in the mitochondrial apoptotic pathway; the pro‐apoptotic B cell lymphoma (BCL)‐2 proteins, BCL‐2 associated x protein and BCL‐2 antagonist killer 1 induce MOMP whereas the anti‐apoptotic BCL‐2 proteins, BCL‐2, BCL‐x_l and myeloid cell leukaemia 1 prevent MOMP from occurring. The release of pro‐apoptotic factors such as cytochrome c from mitochondria leads to formation of a multimeric complex known as the apoptosome and initiates caspase activation cascades. These pathways are important for normal cellular homeostasis and play key roles in the pathogenesis of many diseases. In this review, we will provide a brief overview of the mitochondrial death pathway and focus on a selection of diseases whose pathogenesis involves the mitochondrial death pathway and we will examine the various pharmacological approaches that target this pathway.