Fig. 4

Proposed mechanism of the HSR and its components in motor neurons and astroglia of mSOD1 over-expressing models of ALS. Motor neuron disease initiation and progression is dependent on the molecular pathologies developed in motor neurons (e.g. formation of mSOD1 aggregates or JUNQ) and astroglia (e.g. secretion of unidentified toxic “factors”). The susceptibility of motor neurons to degeneration is likely due to an inability of motor neurons and astroglia to induce a cytoprotective HSR in response to increasing quantities of misfolded proteins (e.g. mSOD1). (1 and 2) HSF1 in motor neurons has a relatively high threshold for activation and the over-expression of mSOD1 and subsequent molecular pathologies do not activate HSF1 nor induce HSF1 binding to DNA. (3) There is no detectable basal expression or up-regulation of Hsps in mSOD1 over-expressing motor neurons, with the exception of (4) Hsp27, which gradually declines with disease progression. (5) Astroglia in mSOD1 over-expressing mice have increased amounts of Hsp27 and αB-c with disease progression; however, the levels of other Hsps are not changed. (6) There have been few investigations regarding HSF1 activation and DNA-binding in astroglia in the context of ALS. Therefore, the capacity of mSOD1 over-expressing astroglia to activate HSF1 and induce an HSR remains unknown. (7) There is increasing evidence that extracellular vesicles containing Hsps are secreted by astroglia, and these vesicles are endocytosed by motor neurons and facilitate transfer of Hsps