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.

Preventive Vitamin A Supplementation Improves Striatal Function in 6-Hydroxydopamine Hemiparkinsonian Rats

“…Additionally, we quantified microglia in the striatum, as reflected by IBA1 staining, since 6-OHDA and dietary vitamin A can act on neuro-inflammatory processes (8,31). In our conditions, quantification of the number of IBA1 + cells, as well as total IBA1 intensity in the striatum did not reveal any significant effect of 6-OHDA or vitamin A supplementation (Supplementary Figure 1).…”

“…First of all, when one is studying vitamin A supplementation, the levels of vitamin A intake have to be precisely controlled since chronic high doses of vitamin A can lead to oxidative stress and toxicity for the liver (8,36,37). In rats, common levels for sufficient retinol intakes range between 5 and 8 IU/g of diet, while vitamin A supplementation ranges from 20 to ∼50 IU/g (31,38,39).…”

“…Yet, if vitamin A is necessary for ALDH1A1 expression, a decreased vitamin A bioavailability may constitute a risk factor for the disease. However, no clear link has been established yet in PD patients between vitamin A function, ALDH1A1 expression and PD symptoms (8).…”

“…Supporting the relevance of vitamin A for PD, vitamin Adeficient rats display motor alterations (9) and conversely, DA neurons degeneration in mouse and rat PD models is prevented by pharmacological administration of retinoic acid or derivatives (10)(11)(12)(13). Further supporting an implication of vitamin A signaling in PD is the observation that the sub-population of DA SNc neurons that is more prone to degenerate expresses the enzyme aldehyde dehydrogenase 1 subtype A1 (ALDH1A1) (8,(14)(15)(16), the synthesis enzyme of retinoic acid. Interestingly, mice lacking ALDH1A1 enzyme or ALDH1A1 + neurons, exhibit motor impairments along with alterations of DA metabolism (17,18).…”

“…Vitamin A (retinol) is a lipophilic vitamin that is critical for brain development and function along life (7). Vitamin A acts through its active metabolite, retinoic acid, that binds to nuclear receptors and modulate gene transcription (8). Supporting the relevance of vitamin A for PD, vitamin Adeficient rats display motor alterations (9) and conversely, DA neurons degeneration in mouse and rat PD models is prevented by pharmacological administration of retinoic acid or derivatives (10)(11)(12)(13).…”