Kleinlogel, S. | bioRxiv Science

bioRxiv2025

Morphological and functional alteration of light perception circuits in AD patients

Disruption of sleep and circadian rhythms is one of the earliest symptoms of Alzheimers disease (AD). Circadian entrainment and modulation of alertness are non-visual responses to light driven by intrinsically photosensitive retinal ganglion cells (ipRGCs). To explore structural and functional changes of ipRGCs and ipRGC circuits in AD, we analyzed the retinas and brains of 13 elderly patients ranging from normal cognition to AD and performed ex vivo extracellular electrophysiological recordings on freshly harvested retinas. While rods and cones were moderately impaired, there was a severe loss of ipRGCs in AD donors. Importantly, the remaining ipRGCs exhibited morphological alterations, hyperexcitability, and were not able to sustain high levels of activation. These changes may be ipRGC subtype-specific and correlated with disease progression. Altered ipRGC circuits and function could contribute to the disruption of sleep and circadian rhythms reported in AD patients. Measuring ipRGC-dependent responses to light could be a promising way to predict or monitor pathological changes in the brain.

neuroscience↗

bioRxiv2023

Functional Optimization of Light-Activatable Opto-GPCRs: Illuminating the Importance of the Proximal C-terminus in G-protein Specificity

G-protein coupled receptors (GPCRs) are the largest family of human receptors that transmit signals from natural ligands and pharmaceutical drugs into essentially every physiological process. One main characteristic of GPCRs is their ability to specifically couple with different families of G-proteins, thereby triggering specific downstream signaling pathways. While an abundance of structural information is available on GPCR interactions with G-proteins, little is known about the GPCR domains functionally mediating G-protein specificity, in particular the proximal C-terminus, the structure which cannot be predicted with high confidentiality due to its flexibility. In this study, we exploited OptoGPCR chimeras between light-gated GPCRs (opsins) and ligand-gated GCPRs to systematically investigate the involvement of the C-terminus steering G-protein specificity. We employed rhodopsin-beta2-adrenoceptor and melanopsin-mGluR6 chimeras. We discovered a dominant role of the proximal C-terminus, dictating G-protein selectivity in the melanopsin-mGluR6 chimera, whereas it is the intracellular loop 3, which steers G-protein tropism in the rhodopsin-beta2-adrenoceptor. From the functional results and structural predictions, melanopsin and mGluR6 use a different mechanism to bRhod and b2AR to couple to a selective G-protein. Collectively, this work adds knowledge to the GPCR domains mediating G-protein selectivity, ultimately paving the way to optogenetically elicited specific G-protein signaling on demand.

cell biology↗