Specific aspartyl and calpain proteases are required for neurodegeneration in C. elegans

Abstract

Necrotic cell death underlies the pathology of numerous human neurodegenerative conditions. In the nematode Caenorhabditis elegans, gain-of-function mutations in specific ion channel genes such as the degenerin genes deg-1 and mec-4, the acetylcholine receptor channel subunit gene deg-3 and the G(s) protein alpha-subunit gene gsa-1 evoke an analogous pattern of degenerative (necrotic-like) cell death in neurons that express the mutant proteins. An increase in concentrations of cytoplasmic calcium in dying cells, elicited either by extracellular calcium influx or by release of endoplasmic reticulum stores, is thought to comprise a major death-signalling event. But the biochemical mechanisms by which calcium triggers cellular demise remain largely unknown. Here we report that neuronal degeneration inflicted by various genetic lesions in C. elegans requires the activity of the calcium-regulated CLP-1 and TRA-3 calpain proteases and aspartyl proteases ASP-3 and ASP-4. Our findings show that two distinct classes of proteases are involved in necrotic cell death and suggest that perturbation of intracellular concentrations of calcium may initiate neuronal degeneration by deregulating proteolysis. Similar proteases may mediate necrotic cell death in humans.

Caspase-independent pathways of hair cell death induced by kanamycin in vivo

“…Localization of activated calpains to membranes may induce membrane rupture, 30 especially in lysosomes with the resultant leakage of cathepsins which in turn can cleave the DNA repair enzyme PARP1, triggering necrotic-or apoptoticlike cell death. 31 In particular, m-calpain maybe an important 32 In agreement with the predominant cellular localization of aminoglycosides in lysosomes, we find the synthesis and activation of the lysosomal protease cathepsin D increased. Lysosomes also sequester iron, 33,34 and the presence of both aminoglycosides and iron could lead to the formation of ROS which in turn cause destabilization of lysosomal membrane.…”

“…Hydrolysis by these two proteases yields different cleavage fragments and results in different forms of cell death. 31,37 Consistent with a calpain-cathepsin action, the 113 kDa enzyme decreased in the nuclei of outer hair cells with kanamycin treatment without generating the fragmentation products associated with caspase actions (89 and 24 kDa). The unchanged level of mRNA for PARP1 further corroborates that kanamycin reduces PARP1 in a protein cleavage process and not by downregulation of the PARP1 gene.…”

Apoptosis and necrosis mediate skeletal muscle fiber loss in age‐induced mitochondrial enzymatic abnormalities

“…Necrosis is neither organized nor executed in a similar manner to apoptosis, and cell death is a consequence of irreparable damage (Henriquez et al ., 2008). Necrosis therefore frequently occurs during pathological conditions including stroke, ischemia, and neurodegenerative disorders (Syntichaki et al ., 2002; Malhi et al ., 2006; Henriquez et al ., 2008). Inflammation is associated with necrosis and not with apoptotic cell death (Scaffidi et al ., 2002).…”

Cell death in the nervous system

“…For example, a non-apoptotic, caspase-independent form that does not resemble type II or type III developmental PCD has been described by Driscoll and her colleagues 42 …”

“…For example, a non-apoptotic, caspase-independent form that does not resemble type II or type III developmental PCD has been described by Driscoll and her colleagues 42 in C. elegans expressing mutant channel proteins such as MEC-4(d). A uniform, necrosis-like cell death -characterized morphologically by membranous whorls not seen in other types of cell death -is triggered by calcium entry, mediated by specific calpains and cathepsins, and inhibited by calreticulin.…”