Heat shock response and ionstasis: axis against neurodegeneration

the phenomenon of " hormesis ". Exposure of organisms to mild stress fortifies them against subsequent, more severe insults. Yet, the relevant molecular mechanisms remain poorly understood. Although heat stroke is often fatal and survivors may suffer permanent neurologic damage, the mechanisms underlying heat stroke-induced cell and tissue injury remain elusive. To gain insight, we employed the nematode Caenorhabditis elegans to simulate hyperthermia [1]. We observed that heat stroke triggers pervasive necrotic cell death and neurodegeneration in C. elegans. Interestingly, preconditioning of animals at mildly elevated temperature protects against subsequent heat-induced damage. The heat shock transcription factor HSF-1 and the small heat shock protein (sHSP) HSP-16.1 mediate cytoprotection after preconditioning. Interestingly, overexpression of hsp-16.1 suppresses necrosis, bypassing the need for ab initio activation of the heat shock response pathway. HSP-16.1 colocalizes with the Ca 2+ /Mn 2+ ATPase PMR-1 in the Golgi. Notably, worms lacking PMR-1 do not benefit from preconditioning and remain susceptible to heat stroke damage. This indicates that the hormetic effect of preconditioning converges on Golgi and the PMR-1 Ca 2+ pump. In addition, loss of pmr-1 abolishes the protective effect of hsp-16.1 overexpression, suggesting that PMR-1 is an important substrate of this sHSP. Interestingly, preconditioning also suppresses cell death inflicted by diverse insults. Notably, this protective mechanism is highly conserved. We found that murine neurons suffer necrosis upon heat stroke, while prior preconditioning prevents death. sHSPs constitute a diverse family of proteins with multiple roles. Several ageing theories suggest that longevity positively correlates with the ability of the cell and the organism to resist stress. Ageing influences both general and organelle-specific stress response pathways [2]. Distinct experimental approaches have identified proteins that are abundant in long-lived worms [3]. Intriguingly, the most consistently represented subset is the sHSP group, including the Editorial HSP-16 family. We propose that HSP-16.1 mediates its protective effect partly by preserving cellular ionic homeostasis, which is perturbed in the stressful context of ageing. How could sHSPs protect under unfavorable conditions? In stressed cells, ATP levels drop significantly leading to fatal aggregation of damaged proteins. sHSPs protect proteins from thermal denaturation and irreversible aggregation in an ATP-independent manner. We propose that sHSPs constitute one of the cell's first lines of defense against cell death. Is the Golgi an organelle to which different hormetic treatments converge? Ischemic/reperfusion brain injury (IRI) is a severe event characterized by ion homeostasis deregulation leading to necrosis. Ischemic preconditioning (IPC) …