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.