This report describes fly models relevant to neuronopathies that are HSPB8-related. The human gene implicated in this disease is HSPB8, which encodes a small heat-shock protein that plays roles in stress tolerance and regulation of autophagy-mediated protein degradation. HSPB8 is implicated in two human diseases with overlapping phenotypes, Charcot-Marie-Tooth disease, axonal, type 2L (CMT2L, FBhh0000946) and neuronopathy, distal hereditary motor, autosomal dominant 2 (HMND2, FBhh0000947). There are multiple related heat-shock proteins in both human and Drosophila. This disease model uses the human HSPB8 gene and the Drosophila Hsp67Bc gene, which meets multiple criteria for functional similarity specifically to HSPB8. RNAi-targeting constructs, alleles caused by insertional mutagenesis, and mutations analogous to human variants implicated in disease have been generated for Dmel\Hsp67Bc.
Multiple UAS constructs of the human Hsap\HSPB8 gene have been introduced into flies, including wild-type and variants implicated in disease. See the 'Disease-Implicated Variants' table below. Variant(s) implicated in human disease tested (as transgenic human gene, HSPB8): the K141E and K141N variant forms have been introduced into flies; these variants are implicated in both CMT2L and HMN2A. Using wild-type Hsap\HSPB8 and a Drosophila model of Machado-Joseph disease (MJD, FBhh0000063), significant rescue of eye phenotypes produced in the MJD model is observed; using the disease-implicated variants, reduced rescue or no rescue is observed.
Available loss-of-function mutations of Dmel\Hsp67Bc do not exhibit obvious deleterious phenotypes. Muscle-specific over-expression of mutations analogous to human variants implicated in HSPB8-related neuronopathies results in deleterious, but somewhat different, phenotypes affecting larval neuromuscular junctions, accumulation of protein aggregates, and/or larval motility. Mutations of Hsp67Bc analogous to variants implicated in human disease have characterized; see the 'Disease-Implicated Variants' table below.
[updated Feb. 2024 by FlyBase; FBrf0222196]
HSPB8 encodes a protein that belongs to the superfamily of small heat-shock proteins containing a conservative alpha-crystallin domain at the C-terminal part of the molecule. [Gene Cards, HSPB8; 2019.02.14]
As a family, the small heat-shock proteins are important in stress tolerance; many exhibit chaperone-like activity in preventing aggregation of target proteins, keeping them in a folding-competent state and refolding them by themselves or in concert with other ATP-dependent chaperones (Bakthisaran et al., 2015; pubmed:25556000).
HSPB8 modulates autophagy-mediated protein degradation in a mouse ALS1 model using SOD1 (Crippa et al., 2010; PMID:20570967).
Many to many: multiple members of this gene family in both species. Human genes include HSPB1, HSPB2, HSPB3, CRYAA, CRYAB, HSPB6, HSPB7, HSPB8, HSPB9, CRYAA2.
Low-scoring ortholog of multiple human small heat-shock genes (many to many). Dmel\Hsp67Bc shares 33% identity and 54% similarity with human HSPB8. Dmel\Hsp67Bc meets multiple criteria for functional similarity specifically to HSPB8 (FBrf0212431).
