June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Characterization of pathological mechanisms during aging of the Prpf31-mutant mouse model of retinitis pigmentosa.
Author Affiliations & Notes
  • Emeline F Nandrot
    Therapeutics, Institut de la Vision, Paris, France
  • Nawel Hadjout
    Therapeutics, Institut de la Vision, Paris, France
  • Déborah Lew
    Therapeutics, Institut de la Vision, Paris, France
  • Abdallah Hamieh
    Therapeutics, Institut de la Vision, Paris, France
  • Footnotes
    Commercial Relationships   Emeline Nandrot, None; Nawel Hadjout, None; Déborah Lew, None; Abdallah Hamieh, None
  • Footnotes
    Support  This study is supported by the French State program "Investissements d'Avenir" managed by the Agence Nationale de la Recherche [LIFESENSES: ANR-10-LABX-65, project grant to EFN].
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 5355. doi:
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      Emeline F Nandrot, Nawel Hadjout, Déborah Lew, Abdallah Hamieh; Characterization of pathological mechanisms during aging of the Prpf31-mutant mouse model of retinitis pigmentosa.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5355.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose : Mutations in the ubiquitously-expressed Pre-mRNA Processing Factors 3, 8, and 31 (PRPF3, 8 and 31) constitute the second most prominent cause of non-syndromic autosomic dominant retinitis pigmentosa (adRP) in humans. We previously determined that young Prpf-mutant animals display abnormal RPE functions and develop a phenotype with age. Despite the difference in pathological timing between patients and corresponding mouse models, human ARPE-19 cells down-regulated for PRPF31 and Prpf31-mutant primary RPE cells display a similar defect in retinal phagocytosis, suggesting this mouse model can be used as a paradigm to identify related pathological processes. Thus, we set out to characterize RPE-related stress pathways occuring during the aging of Prpf31-mutant mice.

Methods : Studies were conducted on 3 to 24-month-old animals in order to dissect the full series of molecular events. Gene and protein expression levels for the mitochondrial respiratory chain and detoxification pathways were assessed by qPCR and immunoblots. Accumulation of lipids was evaluated on histological sections by Oil-Red-O and Luxol Blue stainings.

Results : ND4 (complex I) expression is decreased from 6 months of age in the RPE/Choroid fraction, while CoxIV (complex IV) expression increases. ATP synthase (complex V) expression diminishes in young animals before augmenting after 12 months of age. Expression of the detoxifying enzyme SOD1 (CuZn-SOD, cytosol) increases with age in mutant mice in contrast to wildtype controls. SOD2 (Mn-SOD, mitochondrial matrix) shows less variation of its expression than SOD1. Lipids coloration were validated on control beta5 knockout integrin mouse sections that accumulate lipofuscin and lipids with age. Stainings on Prpf31-mutant sections confirm our hypothesis that Prpf31-mutant RPE cells accumulate more lipid droplets than wildtype littermates during aging.

Conclusions : Our results suggest that mitochondrial defects could contribute to the RPE phenotype. In addition, oxidative processes appear to take place in Prpf31-mutant RPE cells. Taken together, we strongly believe our data will help us decipher the etiology of tissue-specific adRP cases linked to ubiquitously-expressed splicing factors and could contribute to define a new potential common therapeutic approach for all PRPF genes.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.


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