27‐Hydroxycholesterol Drives the Spread of α‐Synuclein Pathology in Parkinson's Disease

Abstract

BackgroundThe 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.ObjectiveThe aim of this study was to determine whether 27‐OHC regulates α‐Syn aggregation and propagation.MethodsPurified 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.Results27‐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.Conclusions27‐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.

Role of the Night-Time Systemic Processes and the Astrocyte Tryptophan-Melatonin Pathway in the Regulation of α-Synuclein and Wider Parkinson’s Disease Pathophysiology

“…As well as dysregulating glutamatergic activity in the SNpc, glutamatergic dysregulation will also significantly modulate cognition in PD via changes in other regions, including the hippocampal CA2 region [70]. Overall, the suppressed capacity of astrocytes to efflux melatonin will dramatically alter the nature of the interactions of SNpc dopamine neurons with their immediate microenvironment as well as in other CNS regions, coupled to the attenuation of melatonin's suppression of α-synuclein, thereby heightening α-synuclein toxicity presynaptically and in mitochondria [71,72]. A number of studies suggest that α-synuclein spread in astrocytes and CNS cells may be dependent upon the heightened levels of hyperlipidemia, perhaps especially raised 27hydroxycholesterol levels, and the 27-hydroxycholesterol modification of mitochondrial α-synuclein [72].…”

“…Overall, the suppressed capacity of astrocytes to efflux melatonin will dramatically alter the nature of the interactions of SNpc dopamine neurons with their immediate microenvironment as well as in other CNS regions, coupled to the attenuation of melatonin's suppression of α-synuclein, thereby heightening α-synuclein toxicity presynaptically and in mitochondria [71,72]. A number of studies suggest that α-synuclein spread in astrocytes and CNS cells may be dependent upon the heightened levels of hyperlipidemia, perhaps especially raised 27hydroxycholesterol levels, and the 27-hydroxycholesterol modification of mitochondrial α-synuclein [72]. Notably, melatonin decreases intestinal lipid absorption, cholesterol synthesis and hyperlipidemia [73,74].…”