alpha-synuclein and 27-hydroxycholesterol

Alzheimer's disease (AD), the most common form of dementia, is characterized histopathologically by the deposition of β-amyloid (Aβ) plaques and neurofibrillary tangles-containing hyperphosphorylated tau protein in the brain. Parkinson's disease (PD), the most common movement disorder, is characterized by the aggregation of α-synuclein protein in Lewy body inclusions and the death of dopaminergic neurons in the substantia nigra. Based on their pathological signatures, AD and PD can be considered as two different disease entities. However, a subpopulation of PD patients also exhibit Aβ plaques, and AD patients exhibit α-synuclein aggregates. This overlap between PD and AD suggests that common pathological pathways exist for the two diseases. Identification of factors and cellular mechanisms by which these factors can trigger pathological hallmarks for AD/PD overlap may help in designing disease-modifying therapies that can reverse or stop the progression of AD and PD. For the last decade, work in our laboratory has shown that fluctuations in the levels of cholesterol oxidation products (oxysterols) may correlate with the onset of AD and PD. In this review, we will provide results from our laboratory and data from literature that converge to strongly suggest the involvement of cholesterol and cholesterol oxidation products in the pathogenesis of AD and PD. We will specifically delineate the role of and the underlying mechanisms by which increased levels of the oxysterol 27-hydroxycholesterol contribute to the pathogenesis of AD, PD, and AD/PD overlap.

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Brain; Cholesterol, Dietary; Disease Models, Animal; Endoplasmic Reticulum Stress; Homeostasis; Humans; Hydroxycholesterols; Lipid Metabolism; Liver X Receptors; Orphan Nuclear Receptors; Parkinson Disease; Plaque, Amyloid; Rabbits

The accumulation and aggregation of α-synuclein (α-Syn) are characteristic of Parkinson's disease (PD). Epidemiological evidence indicates that hyperlipidemia is associated with an increased risk of PD. The levels of 27-hydroxycholesterol (27-OHC), a cholesterol oxidation derivative, are increased in the brain and cerebrospinal fluid of patients with PD. However, whether 27-OHC plays a role in α-Syn aggregation and propagation remains elusive.. The aim of this study was to determine whether 27-OHC regulates α-Syn aggregation and propagation.. Purified recombinant α-Syn, neuronal cultures, and α-Syn fibril-injected mouse model of PD were treated with 27-OHC. In addition, CYP27A1 knockout mice were used to investigate the effect of lowering 27-OHC on α-Syn pathology in vivo.. 27-OHC accelerates the aggregation of α-Syn and enhances the seeding activity of α-Syn fibrils. Furthermore, the 27-OHC-modified α-Syn fibrils localize to the mitochondria and induce mitochondrial dysfunction and neurotoxicity. Injection of 27-OHC-modified α-Syn fibrils induces enhanced spread of α-Syn pathology and dopaminergic neurodegeneration compared with pure α-Syn fibrils. Similarly, subcutaneous administration of 27-OHC facilitates the seeding of α-Syn pathology. Genetic deletion of cytochrome P450 27A1 (CYP27A1), the enzyme that converts cholesterol to 27-OHC, ameliorates the spread of pathologic α-Syn, degeneration of the nigrostriatal dopaminergic pathway, and motor impairments. These results indicate that the cholesterol metabolite 27-OHC plays an important role in the pathogenesis of PD.. 27-OHC promotes the aggregation and spread of α-Syn. Strategies aimed at inhibiting the CYP27A1-27-OHC axis may hold promise as a disease-modifying therapy to halt the progression of α-Syn pathology in PD. © 2023 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Animals; Cholesterol; Humans; Hydroxycholesterols; Mice; Parkinson Disease

Accumulation of the α-synuclein (α-syn) protein is a hallmark of a group of brain disorders collectively known as synucleinopathies. The mechanisms responsible for α-syn accumulation are not well understood. Several studies suggest a link between synucleinopathies and the cholesterol metabolite 27-hydroxycholesterol (27-OHC). 27-OHC is the major cholesterol metabolite in the blood that crosses the blood brain barrier, and its levels can increase following hypercholesterolemia, aging, and oxidative stress, which are all factors for increased synucleinopathy risk. In this study, we determined the extent to which 27-OHC regulates α-syn levels in human dopaminergic neurons, the cell type in which α-syn accumulates in PD, a major synucleinopathy disorder.. Our results show that 27-OHC significantly increases the protein levels, not the mRNA expression of α-syn. The effects of 27-OHC appear to be independent of an action through liver X receptors (LXR), its cognate receptors, as the LXR agonist, GW3965, or the LXR antagonist ECHS did not affect α-syn protein or mRNA levels. Furthermore, our data strongly suggest that the 27-OHC-induced increase in α-syn protein levels emanates from inhibition of the proteasomal degradation of this protein and a decrease in the heat shock protein 70 (HSP70).. Identifying 27-OHC as a factor that can increase α-syn levels and the inhibition of the proteasomal function and reduction in HSP70 levels as potential cellular mechanisms involved in regulation of α-syn. This may help in targeting the correct degradation of α-syn as a potential avenue to preclude α-syn accumulation.

Topics: alpha-Synuclein; Cholesterol; Dopaminergic Neurons; Humans; Hydroxycholesterols; Parkinson Disease; RNA; RNA, Messenger

Loss of dopaminergic neurons and α-synuclein accumulation are the two major pathological hallmarks of Parkinson's disease. Currently, the mechanisms governing depletion of dopamine content and α-synuclein accumulation are not well understood. We showed that the oxysterol 27-hydroxycholesterol (27-OHC) reduces the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, and increases α-synuclein levels in SH-SY5Y cells. However, the cellular mechanisms involved in 27-OHC effects were not elucidated. In this study, we demonstrate that 27-OHC regulates TH and α-synuclein expression levels through the estrogen receptors (ER) and liver X receptors (LXR). We specifically show that inhibition of ERβ mediates 27-OHC-induced decrease in TH expression, an effect reversed by the ER agonist estradiol. We also show that 27-OHC and the LXR agonist GW3965 increase α-synuclein while the LXR antagonist 5α-6α-epoxycholesterol-3-sulfate significantly attenuated the 27-OHC-induced increase in α-synuclein expression. We further demonstrate that LXRβ positively regulates α-synuclein expression and 27-OHC increases LXRβ-mediated α-synuclein transcription. Our results demonstrate the involvement of two distinct pathways that are involved in the 27-OHC regulation of TH and α-synuclein levels. Concomitant activation of ERβ and inhibition of LXRβ prevent 27-OHC effects and may therefore reduce the progression of Parkinson's disease by precluding TH reduction and α-synuclein accumulation.

Topics: alpha-Synuclein; Cell Line, Tumor; Disease Progression; Down-Regulation; Estrogen Receptor alpha; Estrogen Receptor beta; Humans; Hydroxycholesterols; Liver X Receptors; Neuroblastoma; Orphan Nuclear Receptors; Parkinson Disease; Signal Transduction; Tyrosine 3-Monooxygenase; Up-Regulation

Alpha-synuclein is a lipid-binding protein expressed in neurons and oligodendrocytes which is increased in Parkinson's disease. We identified two putative liver X receptor (LXR) response elements in the human alpha-synuclein gene and used synthetic (TO901317, GW3695) and physiological (27-hydroxycholesterol) LXR activators to assess regulation of alpha-synuclein. LXR ligands upregulated alpha-synuclein mRNA by two-five-fold in human SK-N-SH neurons and three-six-fold in human MO3.13 oligodendrocytes. Significant 50% to four-fold induction of alpha-synuclein protein was also detected. Under these conditions, mRNA for LXR-responsive gene ABCA1 was significantly upregulated 15-40-fold and 5-25-fold in neurons and oligodendrocytes, respectively. LXR may, therefore, contribute to the regulation of alpha-synuclein expression in neurons and oligodendrocytes.

Topics: alpha-Synuclein; Blotting, Western; Cell Line; Cell Line, Tumor; DNA-Binding Proteins; Gene Expression Regulation; Humans; Hydrocarbons, Fluorinated; Hydroxycholesterols; Ligands; Liver X Receptors; Neuroblastoma; Oligodendroglia; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfonamides; Up-Regulation

Evidence suggests that environmental and dietary factors may contribute to the pathogenesis of Parkinson's disease (PD). High dietary intake of cholesterol is such a factor that has been shown to increase or decrease the risk of PD. However, because circulating cholesterol does not cross the blood-brain barrier, the mechanisms linking dietary cholesterol to the pathogenesis of PD remain to be understood. In contrast to cholesterol, the oxidized cholesterol metabolites (oxysterols), 24S-hydroxycholesterol (24-OHC) and 27-hydroxycholesterol (27-OHC), can cross the blood-brain barrier and may place the brain at risk of degeneration. In this study, we incubated the human neuroblastoma SH-SY5Y cells for 24 h with 24-OHC, 27-OHC, or a mixture of 24-OHC plus 27-OHC, and have determined effects on tyrosine hydroxylase (the rate-limiting enzyme in dopamine synthesis) levels, alpha-synuclein levels, and apoptosis. We demonstrate that while 24-OHC increases the levels of tyrosine hydroxylase, 27-OHC increases levels of alpha-synuclein, and induces apoptosis. Our findings show for the first time that oxysterols trigger changes in levels of proteins that are associated with the pathogenesis of PD. As steady state levels of 24-OHC and 27-OHC are tightly regulated in the brain, disturbances in these levels may contribute to the pathogenesis of PD.

Topics: alpha-Synuclein; Analysis of Variance; Apoptosis; Cell Line, Tumor; Dopamine; Drug Combinations; Gene Expression Regulation, Neoplastic; Humans; Hydroxycholesterols; In Situ Nick-End Labeling; L-Lactate Dehydrogenase; Neuroblastoma; Norepinephrine; Tetrazolium Salts; Thiazoles; Tyrosine 3-Monooxygenase