Lipid Pathway Dysfunction in Parkinson’s Disease

By Evelyn Ooi, MD

Assistant Professor of Clinical Neurology and Assistant Attending Neurologist, New York Presbyterian Weill Cornell Medical Center

SYNOPSIS: In this large-scale study, the authors used a comprehensive untargeted lipidomic approach to determine the extent to which lipid dysregulation occurs in patients with Parkinson’s disease generally and in mutation carriers of one of the most common Parkinson’s disease risk genes, LRRK2. Further pathway analysis reveals sphingolipid metabolism, insulin signaling, and mitochondrial function as major metabolic pathways dysregulated in Parkinson’s disease.

SOURCE: Galper J, Dean NJ, Pickford R, et al. Lipid pathway dysfunction is prevalent in patients with Parkinson’s disease. Brain 2022;145:3472-3487.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized mainly by the loss of dopaminergic neurons in the nigrostriatal system and by the hallmark pathologic accumulation of alpha-synuclein in the brainstem. Although the exact etiology of PD remains largely unknown, the complex interplay between genetic and environmental factors frequently is invoked. An accumulating body of evidence points toward a significant role of lipids in the pathways leading to PD. Mutation in one of the most common PD risk genes, LRRK2, results in increased LRRK2 kinase activity, which likewise has been implicated in lipid metabolism and/or lipid signaling pathways. However, most research to date has taken a protein-centric approach. In this large-scale study by Galper et al, the authors aimed to better determine the extent to which lipid alterations are present in Parkinson’s disease and in mutation carriers of LRRK2, and to identify the main functional lipid pathways involved.

To this end, the authors carried out untargeted high-performance liquid chromatography-tandem mass spectrometry on serum (n = 221) and cerebrospinal fluid (CSF) (n = 88) samples obtained from a multi-ethnic population from the Michael J. Fox Foundation LRRK2 Clinical Cohort Consortium. This cohort consisted of controls, asymptomatic LRRK2 G2019S carriers, LRRK2 G2019S carriers with PD, and PD patients without a known LRRK2 mutation. Since asymptomatic LRRK2 carriers were younger and PD groups had a higher proportion of males, age and sex were adjusted for where appropriate in analyses.

Using advanced mass spectrometry and LipidSearch software, 31 lipid subclasses comprising 1,118 unique lipid species were identified in serum, with approximately 1,000 serum lipid species per participant analyzed. The main serum lipids that were found to significantly distinguish PD patients and LRRK2 mutation carriers from controls included species of ceramide, triacylglycerol, sphingomyelin, acylcarnitine, phosphatidylcholine, and lysophosphatidylethanolamine. Similar lipidomic studies carried out on CSF samples revealed that sphingolipids and glycerolipids are significantly altered in PD and LRRK2 mutation carrier CSF. No correlations were observed between lipids identified in both serum and CSF. To determine the functional significance of altered lipid species among PD patients and/or LRRK2 mutation carriers, pathway analysis subsequently was carried out via online compound and pathway database. Major metabolic pathways dysregulated in PD were found to include sphingolipid metabolism, insulin signaling, and mitochondrial function. Of note, these same pathways also were found to be dysregulated in serum samples from a second LRRK2 Ashkenazi Jewish cohort (n = 315).

COMMENTARY

Lipids increasingly are understood to have a significant role in the pathological pathways leading to PD. In this study, Galper et al shed further insight into the extent of lipid dysregulation and associated functional and metabolic pathways in PD. Importantly, the metabolic pathways implicated coincide with known PD risk genes that encode enzymes involved in regulation of lipid biosynthesis and activity. These pathways provide yet another promising avenue for future therapeutics. Moreover, as the results of this study demonstrated that lipids significantly discriminate PD patients and LRRK2 G2019S carriers from controls, serum lipid profiles may be of interest in the development of objective diagnostic biomarkers for both genetic and idiopathic PD.

Changes in lipid profile also may prove useful as potential pharmacodynamic biomarker candidates in LRRK2 targeting clinical trials. Further longitudinal study is needed to determine if lipid profile may be predictive of clinical onset of symptoms in asymptomatic LRRK2 mutation carriers or progression of disease.