Abstract
Parkinson’s disease (PD) is a neurodegenerative disease characterized by a progressive loss of dopaminergic neurons from the nigrostriatal pathway, formation of Lewy bodies, and microgliosis. During the past decades multiple cellular pathways have been associated with PD pathology (i.e., oxidative stress, endosomal-lysosomal dysfunction, endoplasmic reticulum stress, and immune response), yet disease-modifying treatments are not available. We have recently used genetic data from familial and sporadic cases in an unbiased approach to build a molecular landscape for PD, revealing lipids as central players in this disease. Here we extensively review the current knowledge concerning the involvement of various subclasses of fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterols, and lipoproteins in PD pathogenesis. Our review corroborates a central role for most lipid classes, but the available information is fragmented, not always reproducible, and sometimes differs by sex, age or PD etiology of the patients. This hinders drawing firm conclusions about causal or associative effects of dietary lipids or defects in specific steps of lipid metabolism in PD. Future technological advances in lipidomics and additional systematic studies on lipid species from PD patient material may improve this situation and lead to a better appreciation of the significance of lipids for this devastating disease.
Highlights
The differential outcome of these studies could be attributed to factors such as age and gender, among others, since lower plasma cholesterol levels have been reported in Parkinson’s disease (PD) male patients of more than 55 years compared to controls [458], a high total cholesterol baseline has been associated with increased risk of PD in subjects of 25–54 years [459], and female PD patients seem to have higher cholesterol levels compared to male PD patients [460]
There is an association between PD and the levels of fatty acyls (SFA, monounsaturated fatty acids (MUFA), polyunsaturatedfatty acids (PUFA), a number of eicosanoids, and acylcarnitine), glycerolipids (MAG, DAG, and TAG), glycerophospholipids (PA, LPA, PE, PS, PC, LPC, PI, PIPx, PG, and CL), sphingolipids (sphingosine(-1P), ceramide, SM, cerebrosides, gangliosides, and sulfatides), sterols and lipoproteins (HDL, low-density lipoproteins (LDL), and very low-density lipoproteins (VLDL))
There is a conspicuous relationship between the folding, aggregation, and distribution of α-synuclein and the lipids that drive some of the neuropathological features of PD
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting 1% of the population above 60 years and up to 4% of individuals in the highest age groups [1]. We found that lipids play a key role in most of the processes that have been (classically) associated with PD (i.e., oxidative stress, endosomal-lysosomal function, endoplasmic reticulum stress, and immune response), and in PD etiology. In agreement with this observation, mutations in the gene encoding the lipid-producing enzyme glucocerebroside (GBA) are associated with familial PD [10,11,12], and multiple single-nucleotide polymorphisms (SNPs) located in other genes involved in lipid metabolism, e.g., SREBF1 [13], DGKQ [14], ASAH1 [15] or SMPD1 [16], have been linked to sporadic PD. Adedpeicptiicotnioonfotfhtehveavraioriuosulsipliipdidstsrturcutcutruersesananddoof faallllththeemmeettaabboolilcicsstteeppssiinnvvoollvveedd iinn tthheeiirr ggeenneerraattiioonn aanndd iinntteerrccoonnvveerrssiioonn((ss)) iiss ggiivveenn iinn FFiigguurreess 22aa,,bb––66aa,,bb,, rreessppeeccttiivveellyy
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