Abstract
Mutations in the photoreceptor outer segment (OS) specific peripherin-2 lead to autosomal dominant retinitis pigmentosa (adRP). By contrast, mutations in the peripherin-2 homolog Rom-1 cause digenic RP in combination with certain heterozygous mutations in peripherin-2. The mechanisms underlying the differential role of peripherin-2 and Rom-1 in RP pathophysiology remained elusive so far. Here, focusing on two adRP-linked peripherin-2 mutants, P210L and C214S, we analyzed the binding characteristics, protein assembly, and rod OS targeting of wild type (perWT), mutant peripherin-2 (perMT), or Rom-1 complexes, which can be formed in patients heterozygous for peripherin-2 mutations. Both mutants are misfolded and lead to decreased binding to perWT and Rom-1. Furthermore, both mutants are preferentially forming non-covalent perMT-perMT, perWT-perMT, and Rom-1-perMT dimers. However, only perWT-perMT, but not perMT-perMT or Rom-1-perMT complexes could be targeted to murine rod OS. Our study provides first evidence that non-covalent perWT-perMT dimers can be targeted to rod OS. Finally, our study unravels unexpected opposing roles of perWT and Rom-1 in rod OS targeting of adRP-linked peripherin-2 mutants and suggests a new treatment strategy for the affected individuals.
Highlights
The tetraspanin peripherin-2 is exclusively expressed in outer segments (OS), specific light detecting compartments of photoreceptors
By analyzing the molecular mechanisms of two Autosomal dominant retinitis pigmentosa (adRP)-linked peripherin-2 mutants, we provide evidence for a novel role of peripherin-2 and its homolog Rom-1 in the pathophysiology of rod photoreceptors
We show for the first time that rod OS targeting of peripherin-2 mutants can be rescued in vivo by simultaneous co-delivery of perWT using rAAV-mediated gene transfer
Summary
The tetraspanin peripherin-2 is exclusively expressed in outer segments (OS), specific light detecting compartments of photoreceptors. Each of these complexes can exist in different equilibria of mono-, di- and tetramers and higher-order oligomers, respectively This high complexity precluded a more accurate investigation of how subunit assembly might influence the rod OS targeting of the single peripherin-2 protein complexes. Other studies demonstrated that perC214S affects homotypic mutant interactions and the heteromerization with Rom-121, 22 Despite these findings, little is known about the specific binding characteristics of this and other peripherin-2 mutants to perWT or Rom-1 in their native environment (e.g. rod OS). The precise contribution of perWT and Rom-1 on binding properties, subunit assembly, and rod OS targeting of the respective perWT-perMT and Rom-1-perMT complexes is not clear Such information is crucial to understand the full complexity of PRPH2-linked adRP and for developing successful treatments for the disease. Only perWT-perMT but not Rom1-perMT complexes could be targeted to rod OS suggesting unexpected opposing roles of peripherin-2 and Rom-1 in rod OS targeting of adRP-linked peripherin-2 mutants
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