Over‐expression of Hsp27 does not influence disease in the mutant SOD1^G93A mouse model of amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a chronic, adult‐onset neurodegenerative disorder characterized by the selective loss of upper and lower motor neurons, resulting in severe atrophy of muscles and death. Although the exact pathogenic mechanism of mutant superoxide dismutase 1 (SOD1) causing familial ALS is still elusive, toxic protein aggregation leading to insufficiency of chaperones is one of the main hypotheses. In this study, we investigated the effect of over‐expressing one of these chaperones, heat shock protein 27 (Hsp27), in ALS. Mice over‐expressing the human, mutant SOD1G93A were crossed with mice that ubiquitously over‐expressed human Hsp27. Even though the single transgenic hHsp27 mice showed protection against spinal cord ischemia, the double transgenic SOD1G93A/hHsp27 mice did not live longer, and did not show a significant delay in the onset of disease compared to their SOD1G93A littermates. There was no protective effect of hHsp27 over‐expression on the motor neurons and on the mutant SOD1 aggregates in the double transgenic SOD1G93A/hHsp27 mice. In conclusion, despite the protective action against acute motor neuron injury, Hsp27 alone is not sufficient to protect against the chronic motor neuron injury due to the presence of mutant SOD1.

The Multicolored World of the Human HSPB Family

“…In cells, however, HSPB1 overexpression did result in some protective effects against aggregate related toxicity, but it only mildly reduced ) or did not reduce (Patel et al 2005 ) mutant SOD1 aggregation. In line with these cellular data, overexpression of HSPB1 showed no (Krishnan et al 2008 ) or only a very mild (Sharp et al 2008 ) protective effect during early stages of disease in SOD-mice. Inversely, HSPB5 knockout mice show no enhanced degeneration when crossed with SOD1 mouse models (Yerbury et al 2013 ).…”

The small heat shock proteins αB-crystallin and Hsp27 suppress SOD1 aggregation in vitro

“…This study was able to confirm the ability of Hsp27 and αB-crystallin to inhibit G93A SOD1 aggregation in vitro. Since previous studies have suggested that over-expression of chaperones is insufficient to attenuate the progression of ALS in mouse models (Krishnan et al 2008), further investigation to clarify the mechanism by which mutant SOD1 escapes the proteostatic machinery might provide clues to a possible treatment for ALS.…”

The Small Heat-Shock Proteins: Cellular Functions and Mutations Causing Neurodegeneration

“…Samples from ALS brains are positive for HSPB1, HSPB5, and Hsp70 (Vleminckx et al 2002, Batulan et al 2003Maatkamp et al 2004), suggesting that Hsps might be connected to the pathogenesis of ALS. However, recent studies showed that ALS mice overexpressing HSPB1 did not have increased life span even though mutant SOD1 aggregates were decreased (Krishnan et al 2008;Sharp et al 2008). …”