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.
Highlights
Huntington’s disease (HD) is an incurable autosomal-dominant genetic disease caused by an abnormal expansion of CAG repeats in exon 1 of the HTT gene, which encodes for the huntingtin protein [1,2]
Previous results from our lab showed that RTP801 levels are increased in brain hoPrevious results from our lab showed that RTP801 levels are increased in brain homogenates obtained from HD patients putamen and cerebellum [29,39]
In human post-mortem hippocampal lysates, we found that RTP801 protein levels were significantly post-mortem hippocampal lysates, we found that RTP801 protein levels were significantly increased in HD patients compared with controls (Figure 1a,b)
Summary
Huntington’s disease (HD) is an incurable autosomal-dominant genetic disease caused by an abnormal expansion (of variable number) of CAG repeats in exon 1 of the HTT gene, which encodes for the huntingtin protein (htt) [1,2]. This expansion confers toxic properties to mutant htt (mhtt), leading to protein misfolding and aberrant aggregation. HD is characterized by a triad of motor, cognitive, and psychiatric symptoms [5,6,7]. Clinical manifestations of unequivocal motor alterations are generally a key Biomolecules 2022, 12, 34.
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