Liver X receptor β protects dopaminergic neurons in a mouse model of Parkinson disease

Abstract

Parkinson disease (PD) is a progressive neurodegenerative disease whose progression may be slowed, but at present there is no pharmacological intervention that would stop or reverse the disease. Liver X receptor β (LXRβ) is a member of the nuclear receptor super gene family expressed in the central nervous system, where it is important for cortical layering during development and survival of dopaminergic neurons throughout life. In the present study we have used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD to investigate the possible use of LXRβ as a target for prevention or treatment of PD. The dopaminergic neurons of the substantia nigra of LXRβ −/− mice were much more severely affected by MPTP than were those of their WT littermates. In addition, the number of activated microglia and GFAPpositive astrocytes was higher in the substantia nigra of LXRβ −/− mice than in WT littermates. Administration of the LXR agonist GW3965 to MPTP-treated WT mice protected against loss of dopaminergic neurons and of dopaminergic fibers projecting to the striatum, and resulted in fewer activated microglia and astroglia. Surprisingly, LXRβ was not expressed in the neurons of the substantia nigra but in the microglia and astroglia. We conclude that LXR agonists may have beneficial effects in treatment of PD by modulating the cytotoxic functions of microglia.midbrain | neurodegeneration | neuroinflammation P arkinson disease (PD) is a common neurodegenerative disorder whose clinical features include tremor, slowness of movement, stiffness, and postural instability (1). PD is characterized by microgliosis, astrogliosis, progressive degeneration of dopaminergic neurons, presence of Lewy bodies in dopaminergic neurons, and α-synuclein accumulation in substantia nigra pars compacta (2). Although there are drugs that alleviate symptoms of PD, chronic use of these drugs results in debilitating side effects (3), and none seems to halt the progression of the disease. The etiology of PD remains unknown, but environmental toxins, genetic factors, and mitochondrial dysfunction are thought to be involved. Neuroinflammation (microglial activation, astrogliosis, and lymphocyte infiltration) results in production of cytotoxic molecules (4-9) that are directly involved in neuronal degeneration. It is now recognized that targeting neuroinflammation is one intervention that can slow down the progression of PD (10).1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that targets rather specifically dopaminergic neurons that are involved in PD; its administration leads to severe and irreversible PD-like syndrome in humans and nonhuman primates, with most of the biochemical and pathological hallmarks of PD (11), i.e., marked loss of dopaminergic neurons, astrogliosis, and activated microglia in the substantia nigra pars compacta (12). In 2002, Wu et al. (13) showed that dopaminergic neurons in the substantia nigra could be protected from MPTP-induced damage by the tetracycline derivative minocycline. This capaci...

Liver X receptor β controls thyroid hormone feedback in the brain and regulates browning of subcutaneous white adipose tissue

“…TSH in turn binds to its receptor TSHR on the thyroid gland, where it stimulates TH synthesis (28). Multiple studies indicate that LXRs play a vital role in the development of brain and are involved in several severe neurodegenerative diseases (24,32), such as Parkinson's disease (33). Here, we discovered that the TSH staining in endocrine cells of anterior pituitary was increased in LXRαβ −/− mice (Fig.…”

“…Although loss of LXRβ leads to resetting of the HPT axis, it is unclear whether or not it will be possible to target LXRβ to treat obesity. LXRβ has many beneficial effects in the brain (24,32,33), and it does not appear to be beneficial to block LXRβ. However, some of the effects of loss of LXRβ on browning of SAT may be independent of the HPT axis.…”

Cholestenoic acids regulate motor neuron survival via liver X receptors

“…Numerous studies in recent years have linked LXR to neuronal degeneration (2,5,(51)(52)(53). These studies have used Lxrb -/-and Lxra -/-Lxrb -/-mice.…”

Liver X receptors alpha and beta promote myelination and remyelination in the cerebellum

“…LXR activation promotes synaptic plasticity and axonal regeneration in stroke patients (11) and is required for dopaminergic neuron differentiation, which is useful for Parkinson's disease treatment (4,20). In Alzheimer's disease, LXR activation increases the number of cholinergic neurons and attenuates cognitive impairment by blocking the inflammatory process (12).…”