In
Rpgrip1−/− and
rd10 mice, augmented HSP70 expression did not demonstrate a protective effect; instead, we observed an accelerated degeneration in the
rd10 retina and no apparent impact in the
Rpgrip1−/− retina. RPGRIP1 functions as a docking site for ciliary proteins at the base of the connecting cilium and likely facilitates trafficking of nascent proteins from the IS into the OS.
38,55–57 With loss of RPGRIP1, RPGR fails to anchor at the base of the connecting cilium and the proper transport and localization of rod and cone opsin are affected.
38 Enhancing the chaperone system does not rescue the phenotype, and no protective effect was observed. The
rd10 mice carry a missense mutation in the gene encoding β-subunit of cGMP phosphodiesterase 6 (
Pde6b).
45 The
rd10 allele produces a hypomorphic PDE6B that is partially defective in assembling into the PDE6αβγ2 holoenzyme with decreased transport to the OS, leading to higher free cGMP, increased channel opening and Ca
2+ influx, and rapid photoreceptor death.
58–60 We were intrigued by the accelerated photoreceptor degeneration in
rd10 retina by HSP70 overexpression. The mutant PDE6B is expressed at low levels in
rd10 retina, exhibits residual catalytic activity, and is partially mislocalized, consistent with a misfolding defect.
58 Increased expression of HSP70 would enhance the quality control mechanisms, which target misfolded proteins,
61 as evident by decreased staining of PDE6B in
rd10;TgHspa1a+ mice (
Fig. 7). Photoreceptor specific chaperone AIPL1
27,28 directly interacts with HSP70 and HSP90,
25,62 forming a chaperone heterocomplex that regulates biosynthesis, stability, and translocation of PDE6 holoenzyme.
26 HSP70 and HSP90 may compete for binding to the client protein PDE6B. We suggest that overexpression of one arm of the chaperone heterocomplex may lead to imbalance of the system, enhancing PDE6B degradation and accelerating photoreceptor degeneration. Thus augmenting chaperone activity might have limited or no effect when dealing with protein-null defects such as
Rpgrip1−/−, and overstimulating the chaperone machinery may accelerate degeneration in specific cases such as
rd10 mice.