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Advanced Neurology Lipid droplets and neurodegenerative disorders

increased accumulation of LDs in brain aging and aging- The neutral lipids, including triacylglycerols and sterol
related NDDs. It is still unclear how dysregulated LDs are esters, are primarily synthesized within the ER. Then,
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involved in overall homeostasis in brain aging and NDDs. triacylglycerols accumulates with the ER, and nucleate into
Further understanding of the regulatory role of LDs may an oil phase, leading to the lens formation. LDs nucleation
provide new insights to reveal the pathogenesis of NDDs. of neutral lipid and PLIN proteins initially occurs in the
Here, we review the current research on the biogenesis ER. After initial nucleation, neutral lipids gradually
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processes and cellular specificity of LDs in CNS. Then, we gather and expand into spherical droplets. Multiple
provide an overview of molecular mechanisms governing proteins are involved in budding process. Seipin regulates
the LDs in neuroinflammation, aging, and NDDs, focusing the nucleation to form a LDs assembly complex. Seipin
on the disturbance of LDs biology in neuroglia. Finally, we also controls the size of LDs and marks the formations
discuss the growing interest on the potential therapeutic sites of LDs in ER, inducing the separation of LDs from
treatments for NDDs in the management of restoring LDs ER to cytoplasm. 10-12 FIT2 is responsible in partitioning
balance and lipid metabolism pathways. neutral lipids during LDs budding. Loss of FIT2 prevents

2. Biogenesis of LDs LDs from leaving from ER to cytosol, and suppresses
triacylglycerols synthesis. Diacylglycerol acyltransferases
Microscopically, LDs size ranges between 0.2 μm and 1 are responsible for the conversion of diacylglycerol to
μm in diameter, even ranging up to 100 μm. The size and triacylglycerol to modify LDs formation, which is the final
number of LDs vary with different cell types, metabolic step of triacylglycerols synthesis. These enzymes also
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conditions, and nutrient status. LDs surface is bound play an important role in axon regeneration by regulation
with phospholipid monolayer membrane. The LDs core of the phospholipid synthesis. After budding, LDs form
is composed of neutral lipids, including triglycerides, membrane bridges with ER, allowing triacylglycerol
sterol esters, acylceramide, and other non-polar lipids transport into LDs. As the wrapped-triacylglycerol
such as cholesterol, diacylglycerol, and monoacylglycerol. gradually accumulates, nascent LDs become separated
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The dysregulation of neutral lipids synthesis may cause from the ER, translocate into cytoplasm as a new organelle,
lipotoxicity, even inducing cellular inflammation, and fuse with other LDs.
autophagy, and apoptosis. A large amount of proteins
are embedded in or coat the LDs surface, which are 3. Pathophysiology of LDs in neurons and
mainly classified into Classes I and II. Class I proteins, neuroglia
“ERTELLED,” including acyl-CoA synthetase long-chain
family member 3, acyltransferases GPAT4, triglyceride In CNS, LDs are actively involved in lipid metabolism and
lipase ATGL/PNPLA2 and UBX structural domain- homeostasis, which is important for the maintenance of
containing protein 8, etc., are generally distributed within normal brain function. The characteristics and functions
ER membrane to feature a V-like hairpin configuration. of LDs of various cell types in CNS are remarkably different
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Class II proteins, “CYTELLED,” are synthesized within the (Figure 2).
cytoplasm and target LDs surface through hydrophobic In neurons, there are low triglyceride levels and limited
domains, including the perilipin (PLIN 1-5) family, LDs formation in normal conditions. It has been reported
CIDEA, and CCT. All those proteins play pivotal roles in that LDs can be found in primary neuron cultures under
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the regulation of LDs homeostasis and metabolism. appropriate conditions. 14,15 The accumulation of LDs
The biogenesis of LDs is a complex but conserved is susceptible to the cellular stress. In neuron, lipids can
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process, including nucleation, growth, budding, and be synthesized de novo. When under oxidative stress
maturation of a separate organelle (Figure 1). There are conditions, neurons can synthesize lipids and store
cellular proteins involved in regulating LDs biogenesis, them in LDs to prevent reactive oxygen species (ROS)
including fat storage-inducing transmembrane proteins 1 toxicity. Neurons can also absorb lipids from the external
and 2 (FIT1 and FIT2), seipin, and lipin. The relative LDs environment. Neuroglia secretes various lipids, including
proteomic involved in biogenesis are termed as LD-related cholesterol, fatty acids, and phospholipids. All those
proteins, which can be divided into four types: perilipin lipids bind to extracellular proteins and can be ingested
family proteins (PLIN1, PLIN2, PLIN3, PLIN4, and into neurons by low-density lipoprotein (LDL) receptors
PLIN5); lipid and energy metabolism-associated proteins and fatty acid transporters. Cholesterol serves important
(HSL, HSC79, ATGL and ACSL); and signaling proteins roles in remodeling of membranes and synaptogenesis
and membrane-trafficking proteins (Rab19 and vimentin). to maintain a high efficiency of neurotransmitter. It
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These proteins are closely associated with LDs formation, can be transported from astrocytes to neurons through
budding, and maturation. apolipoprotein E (ApoE) particles and later endocytosed

Volume 4 Issue 2 (2025) 2 doi: 10.36922/an.5060