Lipid Pathway Dysfunction Is Prevalent in Patients With Parkinson's Disease

Jasmin Galper; Nicholas J. Dean; Russell Pickford; Simon J. G. Lewis; Glenda M. Halliday; Woojin S. Kim; Nicolas Dzamko

Disclosures

Brain. 2022;145(10):3472-3487. 

In This Article

Abstract and Introduction

Abstract

Many genetic risk factors for Parkinson's disease have lipid-related functions and lipid-modulating drugs such as statins may be protective against Parkinson's disease. Moreover, the hallmark Parkinson's disease pathological protein, α-synuclein, has lipid membrane function and pathways dysregulated in Parkinson's disease such as the endosome–lysosome system and synaptic signalling rely heavily on lipid dynamics. Despite the potential role for lipids in Parkinson's disease, most research to date has been protein-centric, with large-scale, untargeted serum and CSF lipidomic comparisons between genetic and idiopathic Parkinson's disease and neurotypical controls limited. In particular, the extent to which lipid dysregulation occurs in mutation carriers of one of the most common Parkinson's disease risk genes, LRRK2, is unclear. Further, the functional lipid pathways potentially dysregulated in idiopathic and LRRK2 mutation Parkinson's disease are underexplored.

To better determine the extent of lipid dysregulation in Parkinson's disease, untargeted high-performance liquid chromatography–tandem mass spectrometry was performed on serum (n = 221) and CSF (n = 88) obtained from a multi-ethnic population from the Michael J. Fox Foundation LRRK2 Clinical Cohort Consortium. The cohort consisted of controls, asymptomatic LRRK2 G2019S carriers, LRRK2 G2019S carriers with Parkinson's disease and Parkinson's disease patients without a LRRK2 mutation. Age and sex were adjusted for in analyses where appropriate. Approximately 1000 serum lipid species per participant were analysed.

The main serum lipids that distinguished both Parkinson's disease patients and LRRK2 mutation carriers from controls included species of ceramide, triacylglycerol, sphingomyelin, acylcarnitine, phosphatidylcholine and lysophosphatidylethanolamine. Significant alterations in sphingolipids and glycerolipids were also reflected in Parkinson's disease and LRRK2 mutation carrier CSF, although no correlations were observed between lipids identified in both serum and CSF. Pathway analysis of altered lipid species indicated that sphingolipid metabolism, insulin signalling and mitochondrial function were the major metabolic pathways dysregulated in Parkinson's disease. Importantly, these pathways were also found to be dysregulated in serum samples from a second Parkinson's disease cohort (n = 315).

Results from this study demonstrate that dysregulated lipids in Parkinson's disease generally, and in LRRK2 mutation carriers, are from functionally and metabolically related pathways. These findings provide new insight into the extent of lipid dysfunction in Parkinson's disease and therapeutics manipulating these pathways may be beneficial for Parkinson's disease patients. Moreover, serum lipid profiles may be novel biomarkers for both genetic and idiopathic Parkinson's disease.

Introduction

Parkinson's disease is a progressive neurodegenerative disorder involving the loss of dopamine-producing neurons in the brain, in conjunction with the pathological accumulation of α-synuclein protein in remaining neurons. The exact cause of Parkinson's disease is unknown; however, genetic studies suggest a disease of complex aetiology resulting from the interplay of many genetic factors and their environmental interactions. Large-scale sequencing studies of Parkinson's disease patients have identified several risk genes, including those with known lipid-related functions.[1–10] In particular, missense mutations in GBA1, which encodes the lipid-metabolizing lysosomal hydrolase glucocerebrosidase, are the most common genetic factors that increase Parkinson's disease risk.[1,4,6,11–14] Polymorphisms in GALC (encoding galactosylceramidase) and ASAH1 (encoding acid ceramidase) and mutations in SMPD1 (encoding acid-sphingomyelinase) have also been linked to Parkinson's disease risk, and like GBA1, encode lysosome enzymes that catabolize sphingolipids.[2,3,7] Additional lipid-related Parkinson's disease risk genes include SREBF1 (encoding sterol regulatory element binding transcription factor 1)[8] that regulates sterol biosynthesis important in cell membrane maintenance[15] and DGKQ (encoding diacylglycerol kinase theta)[5,9,16,17] that mediates the regeneration of phosphatidylinositol from diacylglycerol important in synaptic vesicle formation.[18,19] Thus, Parkinson's disease genetics suggests that dysregulation of lipid homeostasis may contribute to the development of disease. However, the functional impact of genetic variation in lipid-associated enzymes and how this contributes to Parkinson's disease risk remains to be determined.

Apart from their well-known roles in membrane structure, many lipids act as signalling molecules and important regulators of membrane function, allowing for the appropriate curvature and fluidity required for critical cellular processes such as the synaptic vesicle cycle, the endosome–lysosome system and phagocytosis.[20] In addition, decreases in lipid substrate catabolism in the lysosome interfere with aspects of lysosomal function critical for the clearance of neurotoxic proteins, such as α-synuclein. Moreover, α-synuclein binds to lipid membranes, altering their structure and function, and lipid binding to α-synuclein monomers can result in the formation and stabilization of toxic α-synuclein oligomers.[21] Therefore, alterations in lipid species due to dysregulation of lipid-metabolizing enzymes may directly promote Parkinson's disease pathology. Moreover, meta-analyses of targeted lipid studies have indicated that higher total serum triacylglycerol and cholesterol were protective against Parkinson's disease risk,[22] or were higher in controls compared to Parkinson's disease.[23] Such results suggest widespread lipid alterations in Parkinson's disease; however, further characterization of the collective Parkinson's disease lipidome is required to better understand which lipids and their metabolic pathways may be involved in Parkinson's disease.

Another established Parkinson's disease risk gene is leucine-rich repeat kinase 2 (LRRK2).[24,25] Missense mutations in LRRK2 increase the enzyme's activity and although the biological function of LRRK2 remains to be fully elucidated, studies in cell and animal models have implicated LRRK2 in lysosomal function,[26,27] driving substantial interest in the development of small molecule inhibitors of LRRK2 as potential Parkinson's disease therapeutics.[28,29] Lysosomal stress induced by LRRK2 mutations leads to increased levels of the phospholipid di-22:6 bis(monoacylglycerol)phosphate (BMP), which is excreted in the urine. Levels of BMP in the urine are regulated by LRRK2 kinase activity and thus may constitute a pharmacological biomarker in LRRK2 inhibitor clinical trials.[30,31] Moreover, in differentiated human dopamine neurons and astrocyte models, LRRK2 inversely regulates glucocerebrosidase activity, implicating LRRK2 in the same sphingolipid metabolism pathways as glucocerebrosidase.[32,33] Furthermore, altered ceramide metabolism has been observed in the brains of LRRK2 knockout mice.[34] To date, the extent to which lipid dysregulation occurs in general in idiopathic Parkinson's disease patients is unknown, and to be able to specifically compare lipid dysregulation in idiopathic Parkinson's disease to Parkinson's disease patients with LRRK2 mutations may prove highly informative.

To further determine the extent to which lipid alterations are present in Parkinson's disease patients, a comprehensive untargeted lipidomic analysis was performed using serum and CSF from large multisite cohorts of Parkinson's disease patients and matched controls with and without the common LRRK2 G2019S mutation. We hypothesized that altered lipid profiles would be evident in both Parkinson's disease patients with and without the LRRK2 G2019S mutation, and that pathway analysis would identify the most critical pathways impacted by these changes in patients with Parkinson's disease. Such findings may have implications for understanding disease pathogenesis and potential therapeutic pathways, as well as providing promising avenues for biomarker development.

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