Role and Mechanism of Vitamin A Metabolism in the Pathophysiology of Parkinson's Disease

Abstract

Evidence shows that altered retinoic acid signaling may contribute to the pathogenesis and pathophysiology of Parkinson's disease (PD). Retinoic acid is the bioactive derivative of the lipophilic vitamin A. Vitamin A is involved in several important homeostatic processes, such as cell differentiation, antioxidant activity, inflammation and neuronal plasticity. The role of vitamin A and its derivatives in the pathogenesis and pathophysiology of neurodegenerative diseases, and their potential as therapeutics, has drawn attention for more than 10 years. However, the literature sits in disparate fields. Vitamin A could act at the crossroad of multiple environmental and genetic factors of PD. The purpose of this review is to outline what is known about the role of vitamin A metabolism in the pathogenesis and pathophysiology of PD. We examine key biological systems and mechanisms that are under the control of vitamin A and its derivatives, which are (or could be) exploited for therapeutic potential in PD: the survival of dopaminergic neurons, oxidative stress, neuroinflammation, circadian rhythms, homeostasis of the enteric nervous system, and hormonal systems. We focus on the pivotal role of ALDH1A1, an enzyme expressed by dopaminergic neurons for the detoxification of these neurons, which is under the control of retinoic acid. By providing an integrated summary, this review will guide future studies on the potential role of vitamin A in the management of symptoms, health and wellbeing for PD patients.

Keywords: ALDH1A1; Neuroinflammation; RAR RXR receptors; oxidative stress; retinoic acid; vitamin A.

Fig. 1

Chemical structures of the main retinoids metabolized in the body. Retinol (vitamin A) is directly provided by animal sources. Carotenoids, such as β-carotene, are precursors of retinol from vegetable sources that can be converted into retinol by the organism. Retinol is metabolized into retinal by enzymes of the RDHs family, which can also be converted back to retinol. Retinal can be metabolized into 11 cis retinal. A key bioactive metabolite produced from retinal is RA (all trans retinoic acid), which is irreversibly metabolized by a RALDH protein (ALDH1A1 belongs to RALDHs). RA can be metabolized in 11-Cis Retinal, which is an active metabolite in the retina, and in 9-cis RA, another key active metabolite for the brain. Alternatively, retinol can be transformed in 9CDHRA, an endogenous RXR ligand. RDHs, retinol dehydrogenases; RALDHs, retinaldehydes dehydrogenases.

Fig. 2

Model of RA metabolism and signaling in the nigro-striatal pathway. Retinol (vitamin A) is transported in the extracellular fluids by RBP, and internalized into the cells by STRA6. Retinol can also diffuse across the plasma membrane or through other transporters, not yet identified. Retinol is then bound to CRBP and metabolized into retinal by enzymes of the RDHs family. Retinal is further metabolized into RA by a RALDH protein (notably ALDH1A1 in a sub-population of SNc neurons). RA is then transported to the nucleus bound to CRABP protein. In the nucleus, RA binds to RA receptors (RARs), which activate the control of gene expression by RAR/RXR dimers on genes with a RARE sequence in their promoter. Furthermore, as a trans-synaptic factor, RA can travel trans-synaptically from SNc neurons to striatum neurons [24]. From the literature, it is possible that alpha-synuclein may serve as a cargo protein for the trans-synaptic transport of RA [26]. Finally, RA can be degraded by the Cyp26B1 enzyme. RBP, retinol binding proteins; STRA6, transporter stimulated by retinoic acid 6; CRBP, cellular retinol binding protein; CRABP, cellular retinoic acid binding protein; RDHs, retinol dehydrogenases; RALDHs, retinaldehyde dehydrogenases family (including ALDH1A1); RARE, retinoic acid receptor response element.

Fig. 3

Model of the dual role played by ALDH1A1 in the nigro-striatal pathway. ALDH1A1 is involved in the metabolic pathway of RA because it synthesizes RA from retinal. In parallel, ALDH1A1 is involved in catabolic pathway of dopamine because it degrades DOPAL to DOPAC. Considering that RA controls the expression of ALDH1A1 through PITX3, the model proposes that ALDH1A1 expression is controlled by vitamin A bioavailability. SNc, substantia nigra pars compacta; SNR, substantia nigra pars reticulata.

Fig. 4

Proposed roles and mechanisms of vitamin A metabolism in the pathophysiology of Parkinson’s disease. Inset with α-synuclein aggregates from [110].