The Role of HSP70 and Its Co-chaperones in Protein Misfolding, Aggregation and Disease - The Networking of Chaperones by Co-chaperones - page 245

HSP70 and HSP40 Proteins as Modulators of polyQ
Protein Aggregation and Toxicity
In 1998 Cummings et al demonstrated that molecular chaperones could be potent
modulators of polyQ disease (Cummings et al. 1998 ). This report showed that
in a cellular model of spinocerebellar ataxia type 1 (SCA1) overexpression of
the HSP40 protein, hdj-2 (DNAJA1), caused a significant decrease in the inci-
dence of ataxin-1 inclusions. Subsequently, co-expression of hdj-2 (DNAJA1)
was demonstrated to reduce inclusion incidence in a model of spinal bulbar
muscular atrophy (SBMA) (Stenoien et al. 1999 ).The overexpression of either
hdj-1 (DNAJB1) or hdj-2 (DNAJA1) in a cell model of spinocerebellar ataxia
type 3 (SCA3)/Machado-Joseph disease (MJD) suppressed the aggregation and
toxicity of polyQ-expanded full-length or truncated mutant ataxin-3 (Chai et al.
1999 ). Interestingly, not all the studies of HSP40 co-chaperone overexpression
have shown beneficial effects on protein aggregation and inclusion formation in
cells. For example, it has been reported that overexpression of hdj-2 (DNAJA1)
caused increased inclusion formation in a cell model of HD, and had little ef-
fect on inclusion formation in cell models of SBMA (Kobayashi et al. 2000 ;
Wyttenbach et al. 2000 ; Bailey et al. 2002 ). However, hdj-1 (DNAJB1) in com-
bination with HSP70 reduced inclusion incidence and provided cellular protec-
tion, suggesting that members of the HSP70 and HSP40 families might function
together in chaperoning aggregation-prone proteins. There are multiple reports
of the cooperation of HSP70 and HSP40 proteins in reducing inclusion inci-
dence and toxicity in cellular models of polyQ diseases, including HD (Jana
et al. 2000 ; Rujano et al. 2000 ).
It seems likely that HSP40 proteins which are enriched in neuronal tissues, or
have a neuronal specific expression profile, may be particularly relevant in neuro-
degenerative diseases. In particular, HSJ1a (DNAJB2a) has been shown to increase
ubiquitylation and effectively reduce the incidence of polyQ protein aggregation
in both cell models and in vivo models of polyQ and protein misfolding diseases
dependent on its ubiquitin interaction motifs (UIMs) and a functional J domain
(Westhoff et al. 2005 ; Howarth et al. 2007 ; Gao et al. 2011 ; Labbadia et al. 2012 ;
Novoselov et al. 2013 ). The transgenic overexpression of HSJ1a (DNAJB2a) in
the R6/2 mouse model of HD led to improved neurological performance, signifi-
cantly reduced mutant huntingtin aggregation and enhanced solubility dependent
on HSJ1a (DNAJB2a) client binding, ubiquitin interaction and functional co-opera-
tion with HSP70 (Labbadia et al. 2012 ). Interestingly, the overexpression of HSJ1a
(DNAJB2a) in a mouse model of ALS was also recently shown to improve motor
performance and the survival of motor neurons at the late stages of disease progres-
sion (Novoselov et al. 2013 ). HSJ1a (DNAJB2a) was shown to interact with mutant
superoxide dismutase (SOD1) in spinal cord lysates from the transgenic animals
and to suppress SOD1 aggregation. In a neuroblastoma cell model, HSJ1a (DNA-
JB2a) suppressed SOD1 aggregation and enhanced SOD1 ubiquitylation dependent
on a functional J-domain and UIMs.