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other·ophthalmology, glaucoma, preclinical research, biomedical research·PMC10377047

Glaucoma-Associated CDR1 Peptide Promotes RGC Survival in Retinal Explants through Molecular Interaction with Acidic Leucine Rich Nuclear Phosphoprotein 32A (ANP32A)

Biomolecules · 9 authors, 3 centres

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TL;DR

This preclinical study tested a synthetic glaucoma-associated peptide (CDR1) on ex vivo retinal explants. The study found that the CDR1 peptide increased the survival of retinal ganglion cells (RGCs) by interacting with the protein ANP32A.

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Using mass spectrometry, the authors identified the protein acidic leucine-rich nuclear phosphoprotein 32A (ANP32A) as a specific binding target for the CDR1 peptide. The peptide treatment significantly increased RGC viability in a concentration-dependent manner, with 50 µg/mL yielding about a 22% increase and 100 µg/mL yielding about a 31% increase compared to untreated controls. Proteomic analysis revealed the peptide treatment altered the levels of several proteins, including ANP32A interaction partners. The study suggests the neuroprotective mechanism may involve modulating ANP32A function, potentially affecting histone acetylation and the activity of protein phosphatase 2A. The findings suggest the CDR1 peptide is a candidate for further investigation in glaucoma therapy.

STUDY TYPE

other

SPECIALTY

ophthalmology

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AI pipeline

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ORIGINAL PAPER

PMC10377047

Glaucoma-Associated CDR1 Peptide Promotes RGC Survival in Retinal Explants through Molecular Interaction with Acidic Leucine Rich Nuclear Phosphoprotein 32A (ANP32A)

Biomolecules

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ABSTRACT

Abstract Glaucoma is a complex, multifactorial optic neuropathy mainly characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons, resulting in a decline of visual function. The pathogenic molecular mechanism of glaucoma is still not well understood, and therapeutic strategies specifically addressing the neurodegenerative component of this ocular disease are urgently needed. Novel immunotherapeutics might overcome this problem by targeting specific molecular structures in the retina and providing direct neuroprotection via different modes of action. Within the scope of this research, the present study showed for the first time beneficial effects of the synthetic CDR1 peptide SCTGTSSDVGGYNYVSWYQ on the viability of RGCs ex vivo in a concentration-dependent manner compared to untreated control explants (CTRL, 50 µg/mL: p < 0.05 and 100 µg/mL: p < 0.001). Thereby, this specific peptide was identified first as a potential biomarker candidate in the serum of glaucoma patients and was significantly lower expressed in systemic IgG molecules compared to healthy control subjects. Furthermore, MS-based co-immunoprecipitation experiments confirmed the specific interaction of synthetic CDR1 with retinal acidic leucine-rich nuclear phosphoprotein 32A (ANP32A; p < 0.001 and log2 fold change > 3), which is a highly expressed protein in neurological tissues with multifactorial biological functions. In silico binding prediction analysis revealed the N-terminal leucine-rich repeat (LRR) domain of ANP32A as a significant binding site for synthetic CDR1, which was previously reported as an important docking site for protein-protein interactions (PPI). In accordance with these findings, quantitative proteomic analysis of the retinae ± CDR1 treatment resulted in the identification of 25 protein markers, which were significantly differentially distributed between both experimental groups (CTRL and CDR1, p < 0.05). Particularly, acetyl-CoA biosynthesis I-related enzymes (e.g., DLAT and PDHA1), as well as cytoskeleton-regulating proteins (e.g., MSN), were highly expressed by synthetic CDR1 treatment in the retina; on the contrary, direct ANP32A-interacting proteins (e.g., NME1 and PPP2R4), as well as neurodegenerative-related markers (e.g., CEND1), were identified with significant lower abundancy in the CDR1-treated retinae compared to CTRL. Furthermore, retinal protein phosphorylation and histone acetylation were also affected by synthetic CDR1, which are both partially controlled by ANP32A. In conclusion, the synthetic CDR1 peptide provides a great translational potential for the treatment of glaucoma in the future by eliciting its neuroprotective mechanism via specific interaction with ANP32A’s N terminal LRR domain. Keywords: glaucoma, neuroprotection, ANP32A, proteomics, mass spectrometry

CITATION EXPORT

Carsten Schmelter, Kristian Nzogang Fomo, Alina Brueck et al.. Glaucoma-Associated CDR1 Peptide Promotes RGC Survival in Retinal Explants through Molecular Interaction with Acidic Leucine Rich Nuclear Phosphoprotein 32A (ANP32A). Biomolecules. (2023). https://doi.org/10.3390/biom13071161

AUTHORS

9 · 3 CENTRES

Carsten Schmelter, Kristian Nzogang Fomo, Alina Brueck, Natarajan Perumal, Sascha D Markowitsch, Gokul Govind, Thomas Speck, Norbert Pfeiffer, Franz H Grus

1Department of Experimental and Translational Ophthalmology, University Medical Center, Johannes Gutenberg University, 55131 Mainz, Germany; [email protected] (C.S.); [email protected] (K.N.F.); [email protected] (A.B.); [email protected] (N.P.); [email protected] (N.P.)
2Department of Urology and Pediatric Urology, University Medical Center, Johannes Gutenberg University, 55131 Mainz, Germany; [email protected]
3Institute of Physics, Johannes Gutenberg University, 55131 Mainz, Germany; [email protected] (G.G.);