Calcium-dependent protein folding in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by a progressive loss of motor neurons. Although the etiology remains unclear, disturbances in Ca2+ homoeostasis and protein folding are essential features of neurodegeneration. The correct folding of proteins is managed by folding proteins, which are regulated by Ca2+ levels. Therefore, Ca2+-sensitive folding proteins represent an important link between disturbed Ca2+ handling and protein misfolding in amyotrophic lateral sclerosis. In the first part of this review, we focus on Ca2+ handling in the endoplasmic reticulum and mitochondria in terms of their roles in protein misfolding. In the second part, we draw attention to the main Ca2+-sensitive folding proteins that play a role in motor neuron degeneration such as calreticulin and calnexin, which are involved in the folding of glycosylated proteins. In addition, calmodulin and the Ca2+/calmodulin-dependent protein kinase are discussed as one correlation to oxidative stress. The heat shock protein endoplasmin is associated with the anti-apoptotic insulin-like growth factor pathway that is altered in amyotrophic lateral sclerosis. Grp78, which influences Ca2+ homeostasis in the intraluminal endoplasmic reticulum is upregulated in mice models and amyotrophic lateral sclerosis patients and constitutes a core component of the unfolded protein response. Lastly, the protein disulfide isomerase family is responsible for mediating oxidative protein folding in the endoplasmic reticulum. (C) 2013 Elsevier Ltd. All rights reserved.