Substantially elevating the levels of αB‐crystallin in spinal motor neurons of mutant SOD1 mice does not significantly delay paralysis or attenuate mutant protein aggregation

Abstract

There has been great interest in enhancing endogenous protein maintenance pathways such as the heat-shock chaperone response, as it is postulated that enhancing clearance of misfolded proteins could have beneficial disease modifying effects in ALS and other neurodegenerative disorders. In cultured cell models of mutant SOD1 aggregation, co-expression of αB-crystallin (αB-crys) has been shown to inhibit the formation of detergent-insoluble forms of mutant protein. Here, we describe the generation of a new line of transgenic mice that express αB-crys at >6-fold the normal level in spinal cord, with robust increases in immunoreactivity throughout the spinal cord grey matter and, specifically, in spinal motor neurons. Surprisingly, spinal cords of mice expressing αB-crys alone contained 20% more motor neurons per section than littermate controls. Raising αB-crys by these levels in mice transgenic for either G93A or L126Z mutant SOD1 had no effect on the age at which paralysis developed. In the G93A mice, which showed the most robust degree of motor neuron loss, the number of these cells declined by the same proportion as in mice expressing the mutant SOD1 alone. In paralyzed bigenic mice, the levels of detergent-insoluble, misfolded, mutant SOD1 were similar to those of mice expressing mutant SOD1 alone. These findings indicate that raising the levels of αB-crys in spinal motor neurons by 6-fold does not produce the therapeutic effects predicted by cell culture models of mutant SOD1 aggregation.

AAV2/9-mediated overexpression of MIF inhibits SOD1 misfolding, delays disease onset, and extends survival in mouse models of ALS

“…Notably, it was recently shown that overexpressing the chaperone protein hsp110 in neurons extends the survival of SOD1 G85R -YFP and SOD1 G93A mice (51). However, altering the expression levels of other chaperones previously linked to SOD1, including hsp70, hsp90, hsp27, and αB-crystallin, failed to significantly affect the disease course in different mutant SOD1 mouse models (52)(53)(54)(55)(56).…”

Metabolic and Stress Response Changes Precede Disease Onset in the Spinal Cord of Mutant SOD1 ALS Mice

“…Only ALDH2 and CRYAB are consistently differentially regulated between spinal cord and muscle samples for stress response. αB-crystallin (CRYAB) has been extensively studied as a potential treatment for ALS treatment, because over-expression reduced SOD1 aggregates in cell culture models and knockout in SOD1 mutant mice accelerated disease onset (Xu et al, 2015). However, transgenic overexpression of αB-crystallin in SOD1 mutant mouse lines did not slow disease progression or reduce aggregate formation, making it a poor therapeutic target for ALS (Xu et al, 2015).…”

Walking the tightrope: proteostasis and neurodegenerative disease

“…; Xu et al . ). Thus, it remains to be determined whether up‐regulating chaperone levels is a valid therapeutic approach for the treatment of these neurodegenerative diseases.…”

“…Nevertheless, various studies have demonstrated that over-expression of the HSPs can prevent the aggregation and associated toxicity of disease-related proteins, for example, amyloid-b (Hoshino et al 2011), polyglutamineexpanded proteins (Wyttenbach et al 2002;Jiang et al 2012;Ormsby et al 2013); a-synuclein (Auluck et al 2002;McLean et al 2002;Tue et al 2012;Cox et al 2014) (Auluck et al 2002;McLean et al 2002;Tue et al 2012;Cox et al 2014), and superoxide dismutase 1 (Koyama et al 2006;Crippa et al 2010;Novoselov et al 2013); proteins implicated in the pathogenesis of AD, HD, PD, and ALS, respectively. However, others have reported that overexpression of some HSPs has no significant effects on disease progression in mouse models of disease (e.g., Liu et al 2005;Krishnan et al 2008;Shimshek et al 2010;Xu et al 2015). Thus, it remains to be determined whether upregulating chaperone levels is a valid therapeutic approach for the treatment of these neurodegenerative diseases.…”