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Advanced Neurology Lipid metabolism and Parkinson’s disease

to GBA1 mutation) results in impaired clearance of LDs 2.2.4. Lysosomes: An end processing station for lipid
and accumulation of intracellular LDs. Proteins such metabolism
as perilipin-5 (PLIN5) and perilipin-4 (PLIN4) further As the final processing site for lipid metabolism, lysosomes
modulate this interaction: PLIN5 acts as a bridging protein play a key role in the pathological mechanisms of PD.
for mitochondria–LD contact; its downregulation weakens These bilayer membrane-structured organelles regulate
this interaction, impairing FA transport to mitochondria, protein degradation and lipid homeostasis through
triggering β-oxidation substrate deficiency, energetic their acidic environment (pH 4.5–5.0) and a suite of
crisis, and lipotoxicity. 28,47 In addition, the LD surface hydrolytic enzymes. Under physiological conditions,
protein PLIN4 interacts with α-Syn to promote LD lysosomes maintain lipid balance through lipophagy:
accumulation and inhibit mitophagy; the Src homology LDs are encapsulated by autophagosomes and fused with
2B adaptor protein 1 (SH2B1)–heat shock cognate 70 lysosomes, where lysosomal acid lipase (LAL) hydrolyzes
(HSC70)–PLIN4 axis or downregulating PLIN4 reduces triglycerides and acid β-glucosidase (GCase) degrades
LD load, restores mitochondrial homeostasis, and alleviates sphingolipids. Degraded cholesterol is translocated to
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PD-related neurodegeneration. 48-50 Recent studies identify the cytoplasm through NPC1 for membrane synthesis,
the mitochondrial protein mitoguardin-2 (MIGA2) as a a process regulated by mechanistic target of rapamycin
lipid transporter at mitochondria–LD contacts, directly complex 1 (mTORC1): under nutrient sufficiency,
shuttling FAs and phospholipids (e.g., PC and PE) from LDs mTORC1 suppresses ATG, while energy stress activates
to mitochondria to maintain mitochondrial morphology AMP-activated protein kinase (AMPK) to phosphorylate
and LDs dynamics, highlighting lipids as key mediators of Unc-51-like autophagy-activating kinase 1 (ULK1) and
organelle crosstalk in PD. 39
initiate autophagosome formation. In PD, this balance is
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2.2.3. ER and mitochondria crosstalk through disrupted, particularly in patients with GBA1 mutations.
mitochondria-associated membranes: Mediated lipid GBA1 loss-of-function reduces GCase activity, causing
metabolism its substrate glucosylceramide (GlcCer) to accumulate in
lysosomes. GlcCer directly inhibits the V-ATPase proton
Mitochondria-associated membranes (MAMs) are pump, raising lysosomal pH from 4.5 to approximately
“molecular highways” that coordinate lipid and energy 6.0, which inactivates LAL and impairs lipophagy. 20,21,57,58
metabolism. The ER, a core site for calcium storage and In addition, the normal tetramer–monomer balance of
lipid synthesis, connects tightly to mitochondria through α-Syn is disrupted, making it more prone to form easily
MAMs to facilitate the bidirectional exchange of lipids (e.g., aggregated monomers. These α-Syn aggregates co-localize
PE and phosphatidylserine [PS]) and calcium ions (Ca ), with the lysosomal membrane marker lysosomal-
2+
and to fine-tune energy metabolism. 51,52 This exchange associated membrane protein 1 (LAMP1) and form lipid-
is critical for neuronal function: MAM-mediated lipid rich aggregates within lysosomes. Notably, elevated
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transport supports mitochondrial membrane integrity, GCase activity increases lysosome (LAMP1 )–GCase
+
while calcium flux synchronously activates mitochondrial colocalization and reduces LDs (Plin2 ) accumulation,
+
TCA enzymes, coupling lipid oxidation to energy indicating the coordinated regulation of α-Syn and lipid
production. In PD, this balance is disrupted: pathological homeostasis by lysosomes and LDs—an interaction
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α-Syn oligomers bind the major sperm protein domain disrupted in PD.
of vesicle-associated membrane protein-associated
protein B (VAPB) through their N-terminus (1–60 aa), 3. Lipid metabolism mechanisms in PD
disrupting the VAPB–protein tyrosine phosphatase
interacting protein (PTPIP51) complex and widening the 3.1. FA metabolism: Imbalance between
MAM spacing. This structural disintegration of MAMs neuroprotection and toxicity
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has cascading effects: it reduces PE transport efficiency, FA metabolism is a finely regulated process, including the
sharply decreases CL synthesis, disassembles respiratory key steps of FA synthesis, catabolism (β-oxidation), and
chain super complexes, and increases electron leakage. transport, and it involves the catalysis and regulation of
These changes ultimately trigger mitochondrial outer multiple enzymes. Dysregulation in these processes drives
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membrane permeabilization (MOMP) and apoptotic metabolic imbalance, a key feature of PD pathogenesis
cascades, contributing to dopaminergic neuron loss. that links energy deficits, oxidative stress, and α-Syn
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In addition, α-Syn disrupts MAM-mediated lipid aggregation. The brain exhibits unique FA metabolism
metabolism, particularly impairing PE and PS synthesis/ due to its lipid richness and blood–brain barrier (BBB)
conversion, leading to neuronal membrane dysfunction restriction: the BBB limits peripheral lipid entry, rendering
and contributing to synucleinopathies. 54 the central nervous system (CNS) dependent on local lipid

Volume 4 Issue 4 (2025) 34 doi: 10.36922/AN025320086