Amyotrophic Lateral Sclerosis Pathogenesis: A Journey Through the Secretory Pathway

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. Antioxid. Redox Signal. 13, 1955–1989.

Introduction

First Stop: The Endoplasmic Reticulum

• Endoplasmic reticulum: Primary functions

• An emergency exit from ER: The ERAD pathway

• Mild ER stress and the unfolded protein response: Adaptive phase

• Chronic ER stress and the unfolded protein response: Apoptosis phase

• ER alterations in sALS

• ER abnormalities in fALS induced by SOD1 mutations

• Chronic ER stress and apoptosis in fALS

• Blocking the first exit: ERAD dysfunction in fALS

• ER stress in fALS induced by VAP mutations

• TDP-43, FUS=TLS, and abnormal mRNA metabolism in ALS

• Oxidative protein damage in ALS

Second Stop: Golgi Apparatus

• Golgi apparatus: Main functions

• GA fragmentation in sALS

• GA alterations in fALS -induced by SOD1 mutations

• A nonclassical secretory pathway for mutant SOD1

• GA disturbance and the Wobbler mouse

• GA alterations in fALS induced by dynactin mutations

Third Stop: Endocytosis and Vesicle Transport

• Endocytosis and multivesicular endosomes

• Multivesicular endosomes in fALS

• Vesicle transport and fALS: Alsin

• Vesicle transport and fALS: Dynactin

Final Stop: Autophagy

• Autophagy pathways

• Regulation of autophagy

• Autophagy in fALS

• A role of Fig4 mutations in autophagy and ALS

• Homeostatic balance between autophagy and the UPR in ALS

• Autophagy in sALS

• Autophagy as a therapeutic target to treat ALS?

Conclusion