title: Calcium-dependent protein folding in amyotrophic lateral sclerosis.
abstract: 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, Ca(2+)-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 Ca(2+)-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.
authors.affiliation: Hans Berger Department of Neurology, Jena University Hospital, Erlanger Allee 101, 07747 Jena, Germany. tino.prell@med.uni-jena.de
authors.forename: Tino
authors.initials: T
authors.lastname: Prell
authors.forename: Janin
authors.initials: J
authors.lastname: Lautenschläger
authors.forename: Julian
authors.initials: J
authors.lastname: Grosskreutz
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology*; D000818:Animals; D002118:Calcium / Q000502:physiology*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D051379:Mice; D017510:Protein Folding
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D002118:Calcium
keywords: ALS; Calcium; Calreticulin; ER; ERMCC; Endoplasmin; Grp78; NO; Protein misfolding; SOD; SOD1; UPR; amyotrophic lateral sclerosis; endoplasmic reticulum; endoplasmic reticulum–mitochondria–Ca(2+) cycle; nitric oxide; superoxide dismutase; unfolded protein response