NAD salvage pathway machinery expression in normal and glaucomatous retina and optic nerve.
James R TribbleAnna HagströmKenza JusseaumeEmma LardnerRaymond Ching-Bong WongGustav StålhammarPete A WilliamsPublished in: Acta neuropathologica communications (2023)
Glaucoma is the leading cause of irreversible blindness and is a major health and economic burden. Current treatments do not address the neurodegenerative component of glaucoma. In animal models of glaucoma, the capacity to maintain retinal nicotinamide adenine dinucleotide (NAD) pools declines early during disease pathogenesis. Treatment with nicotinamide, an NAD precursor through the NAD salvage pathway, robustly protects against neurodegeneration in a number of glaucoma models and improves vision in existing glaucoma patients. However, it remains unknown in humans what retinal cell types are able to process nicotinamide to NAD and how these are affected in glaucoma. To address this, we utilized publicly available RNA-sequencing data (bulk, single cell, and single nucleus) and antibody labelling in highly preserved enucleated human eyes to identify expression of NAD synthesizing enzyme machinery. This identifies that the neural retina favors expression of the NAD salvage pathway, and that retinal ganglion cells are particularly enriched for these enzymes. NMNAT2, a key terminal enzyme in the salvage pathway, is predominantly expressed in retinal ganglion cell relevant layers of the retina and declines in glaucoma. These findings suggest that human retinal ganglion cells can directly utilize nicotinamide and could maintain a capacity to do so in glaucoma, showing promise for ongoing clinical trials.
Keyphrases
- optic nerve
- optical coherence tomography
- single cell
- poor prognosis
- clinical trial
- induced apoptosis
- endothelial cells
- rna seq
- public health
- diabetic retinopathy
- randomized controlled trial
- ejection fraction
- binding protein
- stem cells
- cell cycle arrest
- big data
- prognostic factors
- mental health
- cell proliferation
- endoplasmic reticulum stress
- bone marrow
- dna methylation
- machine learning
- african american
- health promotion
- human health
- patient reported