HSPB1 mutations causing hereditary neuropathy in humans disrupt non-cell autonomous protection of motor neurons

Abstract

Heat shock protein beta-1 (HSPB1), is a ubiquitously expressed, multifunctional protein chaperone. Mutations in HSPB1 result in the development of a late-onset, distal hereditary motor neuropathy type II (dHMN) and axonal Charcot-Marie Tooth disease with sensory involvement (CMT2F). The functional consequences of HSPB1 mutations associated with hereditary neuropathy are unknown. HSPB1 also displays neuroprotective properties in many neuronal disease models, including the motor neuron disease amyotrophic lateral sclerosis (ALS). HSPB1 is upregulated in SOD1-ALS animal models during disease progression, predominately in glial cells. Glial cells are known to contribute to motor neuron loss in ALS through a non-cell autonomous mechanism. In this study, we examined the non-cell autonomous role of wild type and mutant HSPB1 in an astrocyte-motor neuron co-culture model system of ALS. Astrocyte-specific overexpression of wild type HSPB1 was sufficient to attenuate SOD1(G93A) astrocyte-mediated toxicity in motor neurons, whereas, overexpression of mutHSPB1 failed to ameliorate motor neuron toxicity. Expression of a phosphomimetic HSPB1 mutant in SOD1(G93A) astrocytes also reduced toxicity to motor neurons, suggesting that phosphorylation may contribute to HSPB1 mediated-neuroprotection. These data provide evidence that astrocytic HSPB1 expression may play a central role in motor neuron health and maintenance.

Small heat shock proteins in neurodegenerative diseases

“…Similarly, overexpression of HSPB1 wild type in astrocytes co-cultured with SOD1(G93A) motor neurons was sufficient to attenuate astrocyte-mediated cytotoxicity. However, CMT2/dHMN-associated mutants of HSPB1 (G84R and R136W) failed to provide this non-cell-autonomous protective function (Heilman et al 2017). It requires pointing out though that the R136W mutant was shown to have an overall increased chaperone activity (Almeida-Souza et al 2010;Almeida-Souza et al 2011).…”

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

“…The lack of an overt phenotype in HSPB1-deficient mice [363] suggests that the pathomechanisms of dominant HSPB1 mutations involves a gain-of-function component [352]. However, the loss of cytoprotection is another potential consequence of HSPB1 mutations, which may contribute to the pathomechanism in combination with dominant toxicity [364]. Impaired tolerance to thermal and unfolded protein stress has been observed in patient fibroblasts [365].…”

“…HSPB1 was shown to protect cells from ER-stress-induced apoptosis by facilitating the proteasomal turnover of BIM, and several disease mutants are defective in this respect [322]. Recent research has demonstrated as well that non-cell autonomous protective effects may be altered by the mutations: while wild-type HSPB1 expressed in astrocytes with SOD1 p.G93A protects co-cultured motoneurons from mutant SOD1 toxicity, the p.G84R and p.R136W fail to show such a protective effect [364].…”

The Regulation of the Small Heat Shock Protein B8 in Misfolding Protein Diseases Causing Motoneuronal and Muscle Cell Death

“…In vitro experiments also support this hypothesis, since both αB-crystallin and HSPB1 overexpression are able to suppress SOD1 aggregation (Yerbury et al, 2013). Focusing on HSPB1, its role in ALS is rather controversial; for example, HSPB1 overexpression is beneficial when tested in different SOD1-based ALS cell models (Patel et al, 2005; Krishnan et al, 2006; An et al, 2009; Yerbury et al, 2013; Heilman et al, 2017), but animal model experiments did not confirm this protective role. In its work, Krishnan et al (2008) showed that the ubiquitous over-expression of human HSPB1 in SOD1-G93A mice [double transgenic SOD1(G93A)/hHSPB1 mice] did not affect disease duration, progression, motor neuron degeneration or SOD1 aggregation, although hHSPB1 overexpression alone (single transgenic hHSPB1 mice) protected against spinal cord ischemia (Krishnan et al, 2008).…”