Modulation of mitochondrial and inflammatory homeostasis through RIP140 is neuroprotective in an adrenoleukodystrophy mouse model

Aims: Mitochondrial dysfunction and inflammation are at the core of axonal degeneration in several multifactorial neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, and Parkinson's disease. The transcriptional coregulator RIP140/NRIP1 (receptor-interacting protein 140) modulates these functions in liver and adipose tissue, but its role in the nervous system remains unexplored. Here, we investigated the impact of RIP140 in the Abcd1- mouse model of X-linked adrenoleukodystrophy (X-ALD), a genetic model of chronic axonopathy involving the convergence of redox imbalance, bioenergetic failure, and chronic inflammation. Methods and results: We provide evidence that RIP140 is modulated through a redox-dependent mechanism driven by very long-chain fatty acids (VLCFAs), the levels of which are increased in X-ALD. Genetic inactivation of RIP140 prevented mitochondrial depletion and dysfunction, bioenergetic failure, inflammatory dysregulation, axonal degeneration and associated locomotor disabilities in vivo in X-ALD mouse models. Conclusions: Together, these findings show that aberrant overactivation of RIP140 promotes neurodegeneration in X-ALD, underscoring its potential as a therapeutic target for X-ALD and other neurodegenerative disorders that present with metabolic and inflammatory dyshomeostasis. This study was funded by the Institute of Health Carlos III through projects FIS PI14/01115 and FIS PI17/00134 to M.P.O., FIS PI13/00584 and FIS PI14/00328 to R.P., FIS PI19/0108 to S.F., and FIS PI14/00410, FIS PI17/00916, and FIS PI20/00759 to A.P. and was co-funded by the European Regional Development Fund (ERDF, a way to build Europe). This study was funded by the Institute of Health Carlos III through grants PFIS FI12/00457 to P.R-R. and Miguel Servet program CPII16/00016 to S.F. and co-funded by the European Social Fund (ESF, investing in your future). This study was supported by the European Commission (FP7-241622 to A.P.); the Autonomous Government of Catalonia (2014SGR168 to R.P. and 2017SGR1206 to A.P.); and the Center for Biomedical Research on Rare Diseases (CIBERER), an initiative of the Institute of Health Carlos III (M.R.). Locomotor experiments were performed by the SEFALer unit F5 led by A.P., which belongs to the CIBERER structure. We thank the CERCA Program/Generalitat de Catalunya for institutional support.