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Advanced Neurology Lipid metabolism and Parkinson’s disease

such as inflammatory responses, oxidative stress, and Cholesterol metabolism in PD is dysregulated in both
the disruption of cell membrane structure. 128,129 Such the CNS and peripheral systems. Furthermore, fibroblasts
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disturbances in LPL homeostasis have been implicated from PD patients also exhibit reduced cholesterol
in the pathogenesis of various diseases, particularly biosynthesis due to decreased 3-hydroxy-3-methylglutaryl-
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neurodegenerative disorders. CoA (HMG-CoA) reductase activity. Statins inhibit
In PD, LPC levels exhibit complex regional variations: HMG-CoA reductase, thereby reducing endogenous
reduced in some brain tissues but elevated in others. cholesterol synthesis and modulating neuronal integrity,
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139,140
These changes suggest a bidirectional LPC imbalance synaptic plasticity, and neurotransmitter release.
in PD. Normally, the balance between LPC and α-Syn Moreover, cholesterol metabolism critically regulates
is essential for the physiological function of α-Syn. α-Syn conformation/aggregation through multiple
Disturbance of this balance contributes to PD pathology. mechanisms, as evidenced by the presence of isopentenyl
Activation of the G protein-coupled receptor 35 (GPR35)– diphosphate isomerase (a cholesterol biosynthesis enzyme)
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extracellular signal-regulated protein kinases (ERK) in Lewy bodies. Experimental evidence demonstrates
signaling pathway by LPC disrupts Golgi structure and that the cholesterol 24-hydroxylase (CYP46A1) promotes
impedes the transport of GCase to lysosomes, leading to α-Syn pathology in PD, with clinical studies further
GlcCer accumulation, which facilitates α-Syn aggregation showing elevated levels of both CYP46A1 and its
and exacerbates cognitive impairment. LPC binding enzymatic product 24-hydroxycholesterol (24-OHC, a
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prevents α-Syn conversion to β-sheet oligomers, whereas brain-specific oxysterol) in PD patients—a pathological
mutations in the PLA2 Group VI (PLA2G6) gene interfere process potentially mediated through stimulation of the
with LPL production and impair the interaction between X-box binding protein 1–lymphocyte-activation gene 3
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LPC and α-Syn, thereby promoting α-Syn aggregation and (LAG3) axis. Targeting the CYP46A1–24-OHC axis
neurodegeneration. 132,133 and LAG3 may represent promising disease-modifying
strategies for PD. Furthermore, the incorporation of
Furthermore, LPC exerts pathological effects through
inflammatory pathways. The inflammatory properties of oxidized cholesterol metabolites (e.g., 24-OHC and
27-OHC) into neuronal membrane lipid rafts potently
LPC are exemplified by LPC (16:0)-induced leukocyte promotes the conversion of α-Syn from α-helix to
extravasation and elevation of pro-inflammatory mediators,
in contrast to the anti-inflammatory effects of LPC (20:4) β-sheet conformation and enhances its aggregation
propensity.
143,144
and LPC (22:6). In addition, PLA2 activity is modulated
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by inflammation and can impair mitochondrial function, 4. Discussion
particularly in male patients. In summary, abnormal LPL
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metabolism is a significant contributor to PD pathogenesis, This review systematically outlines the mechanisms by
involving key pathological components, such as α-Syn which lipid metabolism dysregulation acts as a central
aggregation, neuroinflammation, and mitochondrial hub in PD pathogenesis, integrating lipid–organelle
dysfunction. Therefore, elucidating the mechanisms interactions, abnormalities in key lipid pathways (FAs,
underlying abnormal LPL metabolism in PD is crucial for phospholipids, sphingolipids, etc.), and the tripartite
understanding its pathogenesis, developing early diagnostic interplay between lipid metabolic networks and core
markers, and devising new therapeutic strategies. PD pathological mechanisms (e.g., α-Syn aggregation,
mitochondrial dysfunction, and neuroinflammation).
3.5. Cholesterol metabolism: From membrane In PD, lipid–organelle communication is disrupted
rigidity to α-Syn aggregation
primarily through successive breakdown of MCS,
Cholesterol is a crucial steroid component abundant in particularly those between mitochondria and LDs, MAMs,
nerve tissues, particularly in the brain. 135,136 While primarily and lysosomes and LDs. This impairs targeted transport
synthesized in the ER, cholesterol is rapidly translocated of FAs, phospholipids, and calcium ions, resulting in
to various organelles. It plays a key role in maintaining abnormal LD aggregation, mitochondrial dysfunction, and
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plasma membrane stability and fluidity, participating autophagy impairment. LD accumulation stems from
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in the synthesis of steroid hormones, and regulating cell impaired lipophagy (e.g., α-Syn-mediated PLD1 inhibition
signaling. Cholesterol metabolism includes synthesis, and PLIN4–α-Syn interaction). 19,48,50 PLIN5 dysfunction
modification, transportation, and excretion processes, and disrupts mitochondria–LD contact, triggering an energy
its dysregulation alters cholesterol levels, contributing to crisis through reduced FA transport to mitochondria.
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various diseases, including cardiovascular diseases and MAMs, critical for ER-mitochondria lipid exchange, are
neurodegenerative diseases. 137 structurally disrupted by pathological α-Syn, reducing

Volume 4 Issue 4 (2025) 38 doi: 10.36922/AN025320086