Learn more: The UPR and Proteostasis

Amyotrophic Lateral Sclerosis Pathogenesis: A Journey Through the Secretory Pathway
Antioxid. Redox. Signal. 2010, view full abstract in PubMed

Abstract Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motoneuron degenerative disease characterized by the selective loss of motoneurons in the spinal ventral horn, most brainstem nuclei, and the cerebral cortex. Although approximately 90% of ALS cases are sporadic (sALS), analyses of familial ALS (fALS)-causative genes have generated relevant insight into molecular events involved in the pathology. Here we overview an emerging concept indicating the occurrence of secretory pathway stress in the disease process. These alterations include a failure in the protein folding machinery at the endoplasmic reticulum (ER), engagement of the unfolded protein response (UPR), modifications of the Golgi apparatus network, impaired vesicular trafficking, inhibition of protein quality control mechanisms, oxidative damage to ER proteins, and sustained activation of degradative pathways such as autophagy. A common feature predicted for most of these alterations is abnormal protein homeostasis associated with the accumulation of misfolded proteins at the ER, possibly leading to chronic ER stress and neuronal dysfunction. Signs of ER stress are observed even during presymptomatic stages in fALS mouse models, and pharmacological strategies to alleviate protein misfolding slow disease progression. Because the secretory pathway stress occurs in both sALS and several forms of fALS, it may offer a unique common target for possible therapeutic strategies to treat this devastating disease.

Peptides signal mitochondrial stress
Cell Metab 2010, view full abstract in PubMed

The unfolded protein response (UPR) rebalances mitochondrial protein homeostasis upon proteotoxic perturbations. Haynes et al. (2010) show that this retrograde stress signal is based on efflux of peptides derived from damaged proteins from the mitochondrial matrix to the cytosol; this initiates downstream protective responses in the nucleus to restore cellular balance.