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Advanced Neurology Lipid metabolism and Parkinson’s disease

FAs such as monounsaturated FAs (MUFAs) and sphingolipids (e.g., ceramide [Cer]), LDs prevent ER stress
polyunsaturated FAs (PUFAs), exhibit a high propensity and membrane lipid peroxidation. Another key role
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for oxidation under oxidative stress, generating toxic of LDs is serving as an energy reservoir: contrary to the
metabolites (e.g., 4-hydroxynonenal [4-HNE]) that amplify traditional view that neurons rely solely on glucose, recent
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neuronal injury. Moreover, lipid imbalance activates studies reveal that LDs at synaptic terminals act as “backup
microglia and triggers excessive inflammatory responses, energy sources”—during glucose deprivation, triglycerides
creating a vicious cycle that drives neurodegeneration in in LDs are catabolized by the lipase DDHD domain
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PD. 22-25 containing 2 (DDHD2) to sustain synaptic function.
Neuronal LDs are rich in PUFAs (e.g., docosahexaenoic
2.2. Lipid–organelle interactions in PD acid [DHA] and eicosapentaenoic acid), which prevent
Neurons, as highly specialized cells, depend on a dynamic toxic FAs from accumulating in the cytoplasm by
network of lipid–organelle interactions. This network esterifying free FAs into less active and less toxic forms,
facilitates material and energy exchange among four core thus avoiding oxidative damage and lipotoxicity. Abnormal
organelles—LDs, mitochondria, ER, and lysosomes— accumulation of LDs in neurons and glial cells constitutes a
with lipids playing dual roles as both structural bridges hallmark of neurodegenerative diseases, particularly in PD
and signaling molecules. 34-38 Central to this network are pathology, where it disrupts lipid homeostasis. LD-specific
membrane contact sites (MCS), specialized regions where lipophagy is a key mechanism for the cellular clearance
organelles serve as hubs for inter-organelle lipid transport. of LDs and the maintenance of lipid homeostasis. Recent
At MCS, dedicated lipid transfer proteins mediate targeted discoveries identify autophagy-related gene 14 (ATG14)
lipid redistribution from synthetic compartments (e.g., as a receptor on LDs, recruiting autophagosomes to
ER) to recipient organelles (e.g., mitochondria), ensuring degrade LDs and thus initiating lipophagy, presenting a
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the functional integrity of organelles disconnected from promising therapeutic target. Notably, α-Syn inhibits
secretory pathways 39,40 Emerging evidence suggests that PD phospholipase D1 (PLD1) activity, blocking phosphatidic
is not only a classical proteinopathy but also a multifaceted acid production, impairing lipophagic flux, and driving
“organelle communication disorder.” Dysfunction in abnormal LD accumulation—directly linking lipid
MCS—particularly those involving mitochondria, ER, metabolism disorders to early PD pathogenesis. 19
lysosomes, and LDs—may represent an early event in 2.2.2. LD–mitochondria interaction
disease development. Notably, PD-associated mutations
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(including but not limited to phosphatase and tensin Mitochondria play a key role in lipid metabolism as
homolog deleted on chromosome 10-induced kinase 1 the primary energy producers of the cell. 13,14 First, they
[PINK1], β-glucosidase 1 [GBA1], vacuolar protein sorting support lipid synthesis by providing substrates (e.g.,
13 homolog C [VPS13C], and α-Syn [SNCA]) disrupt the acetyl-coenzyme A [acetyl-CoA]) and energy (e.g., ATP)
function of lipid transport proteins and GTPases, thereby through the tricarboxylic acid (TCA) cycle and oxidative
impairing lipid/calcium exchange at critical contact sites, phosphorylation. 15,17 Second, mitochondria receive free
such as mitochondria–lysosomes, ER–mitochondria, and FAs released from LDs and break them down through
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mitochondria–LDs. These defects lead to reactive oxygen β-oxidation to provide energy. However, this balance
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species (ROS) bursts and lysosomal inflammation, both of is disrupted in neurodegenerative diseases, including
which play key roles in the initiation and progression of PD. Saturated FAs accumulated in LDs are converted to
PD pathology. fatty acyl coenzyme A derivatives by acyl coenzyme A
synthetase 4 (ACSL4) and can generate large amounts
2.2.1. LDs as key regulators in PD of lipid peroxides, such as 4-HNE, when catalyzed by
LDs are multifunctional organelles that dynamically arachidonate 15-lipoxygenase (ALOX15). When lipid
regulate lipid homeostasis, extending well beyond the peroxides exceed the scavenging capacity of glutathione
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conventional perception of them as “inert lipid reservoirs.” peroxidase 4 (GPX4), ferroptosis is activated, leading to
As primary intracellular storage sites for neutral lipids (e.g., widespread PUFA peroxidation and plasma membrane
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triglycerides and cholesterol esters), LDs are coated with a collapse.
phospholipid monolayer—primarily phosphatidylcholine Mitochondria-LD interactions are mediated by key
(PC) and phosphatidylethanolamine (PE)—along with proteins: the neuron-specific lipase DDHD2 regulates
associated proteins, which collectively confer unique lipolysis to release FAs from LDs, while carnitine
protective functions. One critical function of LDs is acting palmitoyltransferase 1 (CPT1) transports these FAs into
as a “lipotoxic firewall.” By selectively sequestering excess mitochondria for β-oxidation. In PD, defective DDHD2
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saturated FAs (e.g., palmitic acid [PA]) and neurotoxic function or impaired lysosomal degradation (e.g., due

Volume 4 Issue 4 (2025) 33 doi: 10.36922/AN025320086