Laperle, A. | bioRxiv Science

bioRxiv2025

Dynamic Transcriptomic Remodeling in Human Neural Progenitor Cells Reveals Mechanisms for Vision Preservation in Retinitis Pigmentosa Model

Human neural progenitor cells (hNPCs) have shown promise in slowing down retinal degeneration in animal models and are currently being tested in clinical trials for treating retinitis pigmentosa (RP). However, the status of grafted hNPCs and their interaction with host retinal cells over time is largely unknown. Here, we investigated single-cell transcriptomic changes in grafted hNPCs and host retinal cells following injection into a rodent model for RP. Grafted hNPCs and host retinal cells undergo dynamic transcriptomic changes in the degenerative retinal environment. Grafted hNPCs protect vision through multiple mechanisms, including trophic factor support, modulation of metabolic activity, reduction of apoptosis, oxidative stress, and inflammation, alongside extracellular matrix remodeling. CellChat analysis revealed a progressive decline in intercellular signaling and communication strength between hNPCs and host retinal cells over time. This study indicates that enhancing trophic factor supports and improving host retinal environment are key targets to enable long-term vision preservation.

neuroscience↗

bioRxiv2021

The proSAAS chaperone provides neuroprotection and attenuates transsynaptic α-synuclein spread in rodent models of Parkinson's disease

Parkinsons disease is a devastating motor disorder involving the aberrant aggregation of the synaptic protein synuclein (aSyn) and degeneration of the nigrostriatal dopaminergic tract. We previously showed that proSAAS, a small secreted chaperone protein widely expressed in neurons within the brain, is able to block aSyn-induced dopaminergic cytotoxicity in primary nigral neuron cultures. We show here that coinjection of proSAAS-encoding lentivirus profoundly reduced the motor asymmetry caused by unilateral nigral AAV-mediated human aSyn overexpression. This positive functional outcome was accompanied by significant amelioration of the human aSyn-induced loss of both nigral tyrosine hydroxylase-positive cells and striatal tyrosine hydroxylase-positive terminals, demonstrating clear proSAAS-mediated protection of the nigro-striatal tract. ProSAAS overexpression also reduced the content of human aSyn protein in both the nigra and striatum and reduced the loss of tyrosine hydroxylase protein in both regions. Since proSAAS is a secreted protein, we tested the possibility that proSAAS is able to block the transsynaptic spread of aSyn from the periphery to the central nervous system, increasingly recognized as a potentially significant pathological mechanism. The number of human aSyn-positive neurites in the pons and caudal midbrain of mice following administration of human aSyn-encoding AAV into the vagus nerve was considerably reduced in mice coinjected with proSAAS-encoding AAV, supporting proSAAS-mediated blockade of transsynaptic aSyn transmission. We suggest that proSAAS may represent a promising target for therapeutic development in Parkinsons disease. SignificanceThis paper describes two independent avenues of research that both provide support for the in vivo neuroprotective function of this small chaperone protein. In the first approach, we show that proSAAS overexpression provides remarkably effective protection against dopaminergic neurotoxicity in a rat model of Parkinsons disease. This conclusion is supported both by three independent assays of motor function as well as by quantitative analysis of surviving dopaminergic neurons in brain areas involved in the control of motor function. In the second line of research, we show that in mice, the spread of human synuclein across synapses can be blunted by proSAAS overexpression.

neuroscience↗