BUSCADOR RECOLECTA

RTP801/REDD1 is a stress-responsive protein overexpressed in neurodegenerative diseases such as Alzheimer's disease (AD) that contributes to cognitive deficits and neuroinflammation. Here, we found that RTP801 interacts with HSPC117, DDX1 and CGI-99, three members of the tRNA ligase complex (tRNA-LC), which ligates the excised exons of intron-containing tRNAs and the mRNA exons of the transcription factor XBP1 during the unfolded protein response (UPR). We also found that RTP801 modulates the mRNA ligase activity of the complex in vitro since RTP801 knockdown promoted XBP1 splicing and the expression of its transcriptional target, SEC24D. Conversely, RTP801 overexpression inhibited the splicing of XBP1. Similarly, in human AD postmortem hippocampal samples, where RTP801 is upregulated, we found that XBP1 splicing was dramatically decreased. In the 5xFAD mouse model of AD, silencing RTP801 expression in hippocampal neurons promoted Xbp1 splicing and prevented the accumulation of intron-containing pre-tRNAs. Finally, the tRNA-enriched fraction obtained from 5xFAD mice promoted abnormal dendritic arborization in cultured hippocampal neurons, and RTP801 silencing in the source neurons prevented this phenotype. Altogether, these results show that elevated RTP801 impairs RNA processing in vitro and in vivo in the context of AD and suggest that RTP801 inhibition could be a promising therapeutic approach., This work was supported in part by the grants SAF2017-88812-R and PID2020-119236RB-I00 by MICIU/AEI/10.13039/501100011033 and by 'ERDF A way of making Europe' (from CM), PID2020-119386RB-I00 (from JA), PID2019-106447RB-I00 (from EP-N), PID2020- 113953RB-I00 (from EM), and PID2019-110356RB-I00 (from JF-I and ES).

Huntington's disease (HD) is a neurological disorder caused by a CAG expansion in the Huntingtin gene (HTT). HD pathology mostly affects striatal medium-sized spiny neurons and results in an altered cortico-striatal function. Recent studies report that motor skill learning, and cortico-striatal stimulation attenuate the neuropathology in HD, resulting in an amelioration of some motor and cognitive functions. During physical training, extracellular vesicles (EVs) are released in many tissues, including the brain, as a potential means for inter-tissue communication. To investigate how motor skill learning, involving acute physical training, modulates EVs crosstalk between cells in the striatum, we trained wild-type (WT) and R6/1 mice, the latter with motor and cognitive deficits, on the accelerating rotarod test, and we isolated their striatal EVs. EVs from R6/1 mice presented alterations in the small exosome population when compared to WT. Proteomic analyses revealed that striatal R6/1 EVs recapitulated signaling and energy deficiencies present in HD. Motor skill learning in R6/1 mice restored the amount of EVs and their protein content in comparison to naïve R6/1 mice. Furthermore, motor skill learning modulated crucial pathways in metabolism and neurodegeneration. All these data provide new insights into the pathogenesis of HD and put striatal EVs in the spotlight to understand the signaling and metabolic alterations in neurodegenerative diseases. Moreover, our results suggest that motor learning is a crucial modulator of cell-to-cell communication in the striatum., Ministerio de Ciencia e Innovación (#FPU18/00194, FPU21/02928, PID2020-119236RB-I00, PID2019-106447RB-I00, PID2021-124896OA-I000, PID2020-119386RB-I00, SAF2017-88812-R).
Agència de Gestió d'Ajuts Universitaris i de Recerca (FI-B-00378).
Michael J. Fox Foundation for Parkinson's Research (MJFF-000858, MJFF-000858).
Horizon 2020 Framework Programme (863214).

Extracellular vesicles (EVs) play a crucial role in intercellular communication, participating in the paracrine trophic support or in the propagation of toxic molecules, including proteins. RTP801 is a stress-regulated protein, whose levels are elevated during neurodegeneration and induce neuron death. However, whether RTP801 toxicity is transferred trans-neuronally via EVs remains unknown. Hence, we overexpressed or silenced RTP801 protein in cultured cortical neurons, isolated their derived EVs (RTP801-EVs or shRTP801-EVs, respectively), and characterized EVs protein content by mass spectrometry (MS). RTP801-EVs toxicity was assessed by treating cultured neurons with these EVs and quantifying apoptotic neuron death and branching. We also tested shRTP801-EVs functionality in the pathologic in vitro model of 6-Hydroxydopamine (6-OHDA). Expression of RTP801 increased the number of EVs released by neurons. Moreover, RTP801 led to a distinct proteomic signature of neuron-derived EVs, containing more pro-apoptotic markers. Hence, we observed that RTP801-induced toxicity was transferred to neurons via EVs, activating apoptosis and impairing neuron morphology complexity. In contrast, shRTP801-EVs were able to increase the arborization in recipient neurons. The 6-OHDA neurotoxin elevated levels of RTP801 in EVs, and 6-OHDA-derived EVs lost the mTOR/Akt signalling activation via Akt and RPS6 downstream effectors. Interestingly, EVs derived from neurons where RTP801 was silenced prior to exposing them to 6-OHDA maintained Akt and RPS6 transactivation in recipient neurons. Taken together, these results suggest that RTP801-induced toxicity is transferred via EVs, and therefore, it could contribute to the progression of neurodegenerative diseases, in which RTP801 is involved., Supported in part by grants from Ministerio de Ciencia e Innovación /AEI/10.13039/501100011033/ and ‘FEDER’: SAF2017-88812-R and PID2020-119236RB-I00, from CM; PID2020-119386RB-I00 from JA and PID2019-106447RB-I00 from EP-N. JS-B was supported by a FPU grant from the Spanish Ministry of Science and Innovation (grant #FPU18/00194). NM-F was supported by a FPI grant from the Spanish Ministry of Science and Innovation (grant IBES-2015-072727). PG-S was supported by a FPU grant from the Spanish Ministry of Science and Innovation (grant #FPU21/02928). GC-C was funded by a FI-2021 grant from the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (grant #FI-B-00378). AC-G was supported by a Michael J. Fox Foundation grant (MJFF-000858). Supported also bythe crowdfunding campaign ‘SOS recerca en Parkinson’ via Goteo.org and Portal d’Avall, S.L.