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Advanced Neurology Lipid metabolism and Parkinson’s disease

changes directly impair membrane fluidity and respiratory α-Syn aggregation through multiple mechanisms. Studies
chain function. The A53T-α-Syn mutant significantly have shown that PC (32:0) and PC (34:1) are associated
disrupts the CL maturation pathway by downregulating with Lewy vesicles. The sn-1 position vinyl ether bond of
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CRLS1 expression and inhibiting tafazzin activity, plasmalogen–PE stabilizes the α-Syn N-terminal α-helical
leading to immature CL accumulation and a functionally structure. A reduction in plasmalogen-PE levels in PD
defective phenotype. In addition, the binding of α-Syn causes α-Syn to unfold into a β-sheet conformation and
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oligomers to MAMs inhibits calcium exchange and lipid increases the rate of α-Syn aggregation. 100,101
transfer, leading to disruption of MAM integrity, which
in turn exacerbates CL dyshomeostasis and mitophagy 3.3. Sphingolipid: Drivers of neuroinflammation and
disorders. 27,29 These findings highlight CL metabolism as proteinopathy
a potential therapeutic target, with strategies to restore Sphingolipids, core components of eukaryotic cell
CRLS1/tafazzin activity or reduce CL oxidation under membranes, constitute a complex metabolic network
preclinical investigation. centered on sphingosine as the backbone, encompassing
Cer, sphingomyelin (SM), glycosphingolipids (GSLs),
3.2.2. PC and PE and the signaling molecule sphingosine-1-phosphate
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PC and PE are the two most abundant core structural lipids (S1P). They regulate membrane structural stability (e.g.,
in eukaryotic cell membranes. 90-93 PC accounts for more myelin formation), cell signaling (e.g., apoptosis/survival
than 50% of most eukaryotic cell membrane phospholipids. balance), lysosomal homeostasis, and synaptic plasticity;
It is predominantly distributed in the outer leaflet of the their dysregulation is a well-established risk factor for PD.
plasma membrane and is synthesized through the cytidine The central hub of sphingolipid metabolism is Cer. 102-104 Its
diphosphate (CDP)–choline pathway; its polar head group de novo synthesis begins with the condensation of serine
imparts rigidity to the membrane structure, and PC serves with palmitoyl-CoA in the ER to form 3-ketosphingosine,
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as a precursor for acetylcholine (ACh) production through which is reduced to sphinganine. Sphinganine is then
hydrolysis. 94,95 In contrast, PE is enriched in the inner acylated to dihydroceramide, which is desaturated to
leaflet, generated through the CDP-ethanolamine pathway form Cer, and then converted to SMs or GSLs in the
and by the PS decarboxylase. Its smaller head group and Golgi apparatus. Downstream degradation depends on
tapered molecular structure can facilitate the formation lysosomal enzymes: acid sphingomyelinase hydrolyzes SM
of membrane curvature, which is essential for vesicle to Cer, and GCase catalyzes GlcCer degradation to glucose
trafficking and autophagosome membrane assembly. 93,94 and Cer. 105
Synergistically, PC and PE maintain membrane 3.3.1. Ceramide
asymmetry, fluidity, and transmembrane signaling
efficiency. PC is an ACh precursor, while PE serves as Sphingolipid metabolic disorders are closely associated
with PD. Total Cer and SM levels are significantly
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an essential substrate for mitochondrial CL synthesis. reduced in the anterior cingulate cortex of PD patients,
Together, they regulate neurotransmitter metabolism and with Cer acyl chain lengths shifting toward shorter
energy homeostasis. Dysregulation of PC/PE metabolism species (increased C18:0, decreased C24:1), indicating
alters their content, composition, and distribution, disturbed Cer metabolism. Cer acts as a pro-apoptotic
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potentially affecting membrane stability, permeability, and messenger, and its accumulation impairs mitochondrial
signaling, thereby contributing to disease pathogenesis.
function. Notably, decreasing Cer levels or stimulating
In PD, reduced PC levels impair membrane integrity its β-oxidation improves the PINK1-deficient phenotype,
and neuronal function. Lipidomic analyses have revealed suggesting novel therapeutic targets for PD. Emerging
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a significant PC/PE imbalance in the brains and peripheral evidence reveals that ethanol-induced Cer production
tissues of PD patients. This was evidenced by reduced causes neuronal apoptosis by increasing myeloid cell
levels of PC (34:5), PC (36:5), and PC (38:5) in the brain, leukemia 1S-mediated MAMs dysfunction. Excessive
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and increased levels of PC (44:5) and PC (44:6) alongside sphingosine kinase 1 (SPHK1) expression is associated
reduced levels of PC (35:6) and PE (34:1) in plasma. 96,97 with PD; drugs such as pramipexole and fingolimod
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In 6-hydroxydopamine (6-OHDA)-treated rats, most PC (FTY720) ameliorate 1-methyl-4-phenyl-1,2,3,6-
levels in the substantia nigra were decreased. 93,98 Meanwhile, tetrahydropyridine (MPTP)-induced dopaminergic
lysophosphatidylcholine (LPC) levels exhibited biphasic neuron loss in PD mice through Akt/SPHK1 activation,
changes—elevated neurotoxic species such as LPC (16:0) wherein SPHK1 catalyzes sphingosine conversion to
and LPC (18:1), and decreased neuroprotective species. 93,98 S1P. In PD, disorders of sphingolipid metabolism drive
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Furthermore, PC/PE metabolic disorders drive pathological progressive loss of dopaminergic neurons through a triple

Volume 4 Issue 4 (2025) 36 doi: 10.36922/AN025320086