Durso, C. | Search bioRxiv

bioRxiv2026

Cell vulnerability within the sublaterodorsal tegmental nucleus underlies REM sleep behaviour disorder in prodromal α-synucleinopathy

REM sleep behaviour disorder (RBD) is a prodromal manifestation of -synucleinopathies such as Parkinsons disease. Evidence suggests that degeneration of REM sleep regulating neurons in the sublaterodorsal tegmental nucleus (SLD) could give rise to RBD, yet the specific cellular populations involved and their contribution to synucleinopathy progression remain unclear. Here, we investigated the role of defined SLD cell types in RBD pathogenesis. Using viral vector and fibril-based models of -synucleinopathy, we show that -synuclein pathology in SLD neurons triggers RBD in mice. Notably, glutamatergic SLD neurons are selectively vulnerable to synucleinopathy and the loss of these cells correlates with RBD severity. Propagation of synucleinopathy from the SLD to midbrain and forebrain structures leads to the emergence of neurological deficits associated with Parkinsons disease. These findings establish that SLD neurons are critical substrates for RBD and provide insight into the cellular mechanisms at play in the early stages of synucleinopathies.

neuroscience↗

bioRxiv2026

Structural basis of chaperone mechanisms in cells and the evolutionary emergence of the protein world

How chaperones mediate protein folding in the crowded cell environment remains poorly understood. To gain insight, we developed CHAP-SEQ to examine how chaperones affect protein folding in cells at high throughput and amino acid resolution. Performing CHAP-SEQ using three chaperone proteins and one chaperone RNA reveals distinct modes of folding assistance. Chaperone proteins act preferentially on hydrophobic core residues, whereas chaperone RNA primarily targets structural or dynamic signatures. Furthermore, while the chaperone RNA has little preference for clients baseline foldability, the chaperone proteins favor clients with greater intrinsic foldability. These differences are consistent with an evolutionary hypothesis in which greater chaperone complexity played a role in the formation of stable hydrophobic cores, suggesting a potential link between chaperone function and the evolution of protein folding.

biochemistry↗