RTP801/REDD1 Is Involved in Neuroinflammation and Modulates Cognitive Dysfunction in Huntington’s Disease

Abstract

RTP801/REDD1 is a stress-regulated protein whose levels are increased in several neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s diseases (HD). RTP801 downregulation ameliorates behavioral abnormalities in several mouse models of these disorders. In HD, RTP801 mediates mutant huntingtin (mhtt) toxicity in in vitro models and its levels are increased in human iPSCs, human postmortem putamen samples, and in striatal synaptosomes from mouse models of the disease. Here, we investigated the role of RTP801 in the hippocampal pathophysiology of HD. We found that RTP801 levels are increased in the hippocampus of HD patients in correlation with gliosis markers. Although RTP801 expression is not altered in the hippocampus of the R6/1 mouse model of HD, neuronal RTP801 silencing in the dorsal hippocampus with shRNA containing AAV particles ameliorates cognitive alterations. This recovery is associated with a partial rescue of synaptic markers and with a reduction in inflammatory events, especially microgliosis. Altogether, our results indicate that RTP801 could be a marker of hippocampal neuroinflammation in HD patients and a promising therapeutic target of the disease.

RTP801 Mediates Transneuronal Toxicity via Extracellular Vesicles by Affecting Their Protein Cargo and Abrogating Their Trophic Effect

“…In line with this, downregulation of RTP801 in AD and HD mouse models prevents cognitive de cits and neuroin ammation 45,50 .…”

“…Dendritic branching defects in mature neurons have devastating consequences on neuronal function and survival and are common features in patients suffering from neurodegenerative diseases 145 . The fact that increased levels of RTP801 are found in PD, AD and HD human postmortem brains, and contribute to neuron impairment in disease mouse models 45,50 , suggests that RTP801 could be an active player in spreading neurodegeneration via EVs and therefore, a potential future target in the treatment of neurodegeneration.…”

STAT3 and REDD1: an unconventional story of gene repression

“…Expression of REDD1 is altered in a vast range of pathologies, from inflammatory diseases to cancer and neurodegenerative disorders. For instance, we have described that REDD1 is upregulated in postmortem brains of patients with Parkinson's (PD) [9], Huntington's (HD) [15] and AD [16], and it has been linked to increased neuroinflammation and cognitive deficits in both HD [17] and AD [16] mice models. Interestingly, selective knockdown of REDD1 in hippocampal neurons with shRNA‐containing AAV particles ameliorates cognitive deficits as well as diminishes astrocytes‐ and microglia‐mediated neuroinflammation in a murine model of HD [16] and AD [15].…”

siRNA incorporated in slow-release injectable hydrogel continuously silences DDIT4 and regulates nucleus pulposus cell pyroptosis through the ROS/TXNIP/NLRP3 axis to alleviate intervertebral disc degeneration

“…DNA damage-inducible transcript 4 (DDIT4) is an evolutionarily conserved protein that has low expression under basal conditions, but is overexpressed when cells are stimulated by oxidative stress, endoplasmic reticulum stress, and hypoxia. 10 , 11 Subsequent independent studies have reported that DDIT4 is involved in various diseases, including Alzheimer’s disease and Parkinson’s disease, 12 myocardial ischaemia/reperfusion injury, 13 and osteoarthritis. 14 Nevertheless, the role of DDIT4 in IVDD warrants further exploration.…”