Nuclear Receptors as Therapeutic Targets for Neurodegenerative Diseases: Lost in Translation

Abstract

Neurodegenerative diseases are characterized by a progressive loss of neurons that leads to a broad range of disabilities, including severe cognitive decline and motor impairment, for which there are no effective therapies. Several lines of evidence support a putative therapeutic role of nuclear receptors (NRs) in these types of disorders. NRs are ligand-activated transcription factors that regulate the expression of a wide range of genes linked to metabolism and inflammation. Although the activation of NRs in animal models of neurodegenerative disease exhibits promising results, the translation of this strategy to clinical practice has been unsuccessful. In this review we discuss the role of NRs in neurodegenerative diseases in light of preclinical and clinical studies, as well as new findings derived from the analysis of transcriptomic databases from humans and animal models. We discuss the failure in the translation of NR-based therapeutic approaches and consider alternative and novel research avenues in the development of effective therapies for neurodegenerative diseases. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 59 is January 6, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

“…As we included tumor and paired normal liver samples from 159 HCC patients for investigation at protein level here, the sample size is much larger than the previous study that included 46 HCC patients (Dietrich et al, 2019), and the results are reliable. In addition, considering the variety of regulatory factors implicated in the process of translation (Grafanaki et al, 2019;Moutinho et al, 2019;Kim et al, 2020), it is understandable to see the inconsistence between the mRNA and protein levels of specific genes. As no significant correlation of NRAS with MKI67 was shown at protein level in HCC, further studies were needed to investigate the specific functions of NRAS in HCC.…”

Nuclear receptor NHR-49 promotes peroxisome proliferation to compensate for aldehyde dehydrogenase deficiency inC. elegans

“…Additional natural and synthetic PPAR ligands have been actively tested as potential treatments for neurologic disorders (Fidaleo et al, 2014;Moutinho et al, 2019). It is conceivable that the same ligands can be repurposed to benefit Sjögren-Larsson Syndrome patients.…”

The Role of APOE4 in Disrupting the Homeostatic Functions of Astrocytes and Microglia in Aging and Alzheimer’s Disease

“…APOE is a lipoprotein that normally facilitates lipid transport between cells (Mahley, 1988). APOE transcription is activated by liver X receptor (LXR) and peroxisome proliferator-activated receptor γ (PPARγ), transcription factors that regulate lipid homeostasis and inflammation (Laffitte et al, 2001; Akiyama et al, 2002; Liang et al, 2004; Mandrekar-Colucci et al, 2012; Moutinho et al, 2019). In the lipid-rich brain, APOE is predominantly expressed by astrocytes and microglia, and perhaps in limited circumstances by neurons (Boyles et al, 1985; Pitas et al, 1987; Uchihara et al, 1995; Nakai et al, 1996; Xu et al, 1998, 2006).…”