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Advanced Neurology Lipid metabolism and Parkinson’s disease

cascade of “α-Syn pathology–mitochondrial dysfunction– protective mechanism in PD pathology. On the other hand,
neuroinflammation.” GCase mutations increase PD risk, GM1 exhibits significant anti-inflammatory properties,
and its substrate GlcCer acts as a scaffold to promote α-Syn suppressing pro-inflammatory responses in microglia
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oligomerization. As discussed in Section 2.2.4, GlcCer in response to inflammatory stimuli. This function
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accumulation also leads to lysosomal damage, further depends on its sialic acid residues and lipid tail structure.
exacerbating microglia-mediated inflammation and Conversely, GM3 demonstrates pro-inflammatory activity,
neuronal loss. In addition, thyroid hormone receptor amplifying neuroinflammation and further exacerbating
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interactor 12 (TRIP12) acts as the E3 ubiquitin ligase for PD progression. 113,118
GCase, promoting its degradation by ubiquitinating the Age factor is also associated with changes in gangliosides.
K293 residue; inhibiting TRIP12 restores GCase activity, Research indicates that GM1 and GD1a levels decline with
reduces α-Syn pathology, and protects neurons. 112 age in non-CNS tissues of normal mice, coinciding with
3.3.2. Gangliosides GM1 and GM3: Angels and deteriorating motor and cognitive functions. This suggests
demons in PD that age-related reduction in gangliosides may constitute
a significant factor in the development of peripheral
Gangliosides are a class of GSLs primarily found on symptoms in PD. 122
neuronal cell membranes, characterized by one or more
sialic acid residues within their molecular structure. They Regarding therapeutic strategies, research has also
play a pivotal role in maintaining the structural integrity explored non-invasive routes for ganglioside administration.
of nerve cells, signal transduction, and cell recognition. Intranasal infusion of GD3 and GM1 in the PD mouse
The equilibrium of ganglioside metabolism is vital for model significantly reduced α-Syn levels and restored
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neuronal survival and functional maintenance. Disruption tyrosine hydroxylase expression. This finding implies
of this equilibrium is closely associated with the onset a potential mechanism by which modulating chromatin
and progression of various neurodegenerative diseases, states could alleviate the accumulation of neurotoxic
particularly playing a significant role in the pathogenesis proteins and restore neuronal functions, offering novel
of PD. 113-115 therapeutic insights into PD treatment. Furthermore, mice
with GM1 synthase deficiency (accompanied by GM3
Within the context of lipid metabolism, gangliosides are synthase dysfunction) exhibited pronounced motor and
considered pivotal molecules driving neurodegeneration short-term spatial memory impairments. Exogenous GM1
in PD. As two representative classes of gangliosides, GM1 replacement therapy markedly improved these deficits,
and GM3 exhibit markedly opposing functional roles in further supporting GM1’s therapeutic potential in GM3-
PD pathogenesis: GM1 is considered neuroprotective, related metabolic disorders such as PD. In summary,
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earning it the epithet “angel,” while GM3 predominantly GM1 and GM3 play opposed roles in the pathogenesis
promotes pathological progression, assuming the role of and progression of PD. Balancing their regulation may
“demon.” 116-118 Disruptions in their expression levels or represent a novel therapeutic target for future disease-
metabolic equilibrium directly contribute to dopaminergic modifying interventions.
neuron loss and abnormal α-Syn aggregation, thereby
accelerating disease progression. 3.4. Lysophospholipids
In PD, genes associated with GM1 synthesis Lysophospholipids (LPLs) are a class of
(e.g., B3GALT4 and ST3GAL2) exhibit reduced expression, monoacylglycerophospholipids, mainly including LPC,
leading to diminished GM1 production and subsequently lysophosphatidylethanolamine, and lysophosphatidic acid.
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impairing neuronal health. Chiricozzi et al. investigated These bioactive lipids are generated through phospholipase
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the therapeutic potential of GM1 oligosaccharides in A2 (PLA2)-mediated hydrolysis of PC, a process that
a B4galnt1 mouse model of PD. They found that simultaneously releases free FAs. The liberated free FAs
+/−
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administration of GM1 oligosaccharide effectively can be further metabolized to pro-inflammatory mediators
penetrated the BBB to reach the brain and significantly (e.g., prostaglandins and leukotrienes) or oxidized lipids
ameliorated PD-related pathological features, including (e.g., hydroxyeicosatetraenoic acids [HETEs]), thereby
restored motor function, reduced abnormal α-Syn levels, initiating a “lipid-inflammatory” cascade network. LPLs
and recovery of tyrosine hydroxylase expression and affect neuronal excitability and synaptic transmission by
neurotransmitter concentrations. Furthermore, Kumar regulating cell membrane fluidity, ion channel activity, and
et al. demonstrated the colocalization of GM1 and α-Syn G protein-coupled receptor signaling. 126,127 Dysregulation
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within neuronal cytoplasm, revealing that GM1 effectively of LPL metabolism significantly alters their levels
inhibits α-Syn aggregation and thereby clarifies its in vivo, potentially triggering pathological processes,

Volume 4 Issue 4 (2025) 37 doi: 10.36922/AN025320086