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Advanced Neurology Lipid metabolism and Parkinson’s disease

penetration for lipid-targeted drugs, also warrant further Author contributions
investigation. From a therapeutic perspective, targeting
lipid metabolism offers multiple avenues: restoring MCS Conceptualization: Ye Xi, Sheng-Xi Wu
Writing–original draft: Ming-Ming Wang, Xiao-Min Wen
function to normalize lipid transport, enhancing lipophagy Writing–review & editing: All authors
through ATG14 activation or PLD1 inhibition, modulating
key enzymes (e.g., CRLS1, GCase, and CYP46A1), and Ethics approval and consent to participate
regulating SCFA levels through gut microbiota modulation.
Figure 1 summarizes these mechanisms, highlighting lipid Not applicable.
metabolism as a unifying target for stabilizing energy Consent for publication
metabolism, reducing oxidative stress, and inhibiting
α-Syn aggregation in PD. Not applicable.
Disorders of sphingolipid metabolism are centered Availability of data
on Cer, and GlcCer accumulates due to defective GCase
function, forming a vicious cycle with α-Syn aggregation Not applicable.
by impairing V-ATPase function. Abnormal lipid References
26
metabolism also triggers neuroinflammation through
multiple pathways. For example, a bidirectional LPC 1. Björklund A, Björklund T, Kirik D. Gene therapy for
dopamine replacement in Parkinson’s disease. Sci Transl
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2. Mollenhauer B, Von Arnim CAF. Toward preventing
5. Conclusion Parkinson’s disease. Science. 2022;377(6608):818-819.
Lipid metabolism dysregulation activates microglia, doi: 10.1126/science.add7162
triggering excessive inflammation, which, synergistically 3. Ben-Shlomo Y, Darweesh S, Llibre-Guerra J, Marras C, San
with oxidative stress, mitochondrial dysfunction, α-Syn Luciano M, Tanner C. The epidemiology of Parkinson’s
aggregation, and aberrant organelle communication, forms disease. Lancet. 2024;403(10423):283-292.
a mutually reinforcing pathological loop. Clarifying these doi: 10.1016/S0140-6736(23)01419-8
mechanisms will advance PD therapeutics by identifying
lipid-centric targets to break this cycle and preserve 4. Wu KM, Xu QH, Liu YQ, et al. Neuronal FAM171A2
neuronal function. mediates α-synuclein fibril uptake and drives Parkinson’s
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Acknowledgments doi: 10.1126/science.adp3645
None. 5. Schmidt S, Luecken MD, Trümbach D, et al. Primary cilia and
SHH signaling impairments in human and mouse models of
Funding Parkinson’s disease. Nat Commun. 2022;13(1):4819.
This work was funded by the Natural Science Foundation doi: 10.1038/s41467-022-32229-9
of China (82571429 to Y.X., 82221001 to S.W.), the 6. Sampson TR, Debelius JW, Thron T, et al. Gut microbiota
Natural Science Basic Research Program of Shaanxi regulate motor deficits and neuroinflammation in a model
(2024JC-YBQN-0774 to Y.X.), and the Open Fund of Key of Parkinson’s disease. Cell. 2016;167(6):1469-1480.e12.
Laboratory of Clinical Neurology, Ministry of Education doi: 10.1016/j.cell.2016.11.018
(2025A02 to Y.X.).
7. Burtscher J, Moraud EM, Malatesta D, Millet GP, Bally JF,
Conflict of interest Patoz A. Exercise and gait/movement analyses in treatment
and diagnosis of Parkinson’s disease. Ageing Res Rev.
Sheng-Xi Wu is an Associate Editor of this journal but 2024;93:102147.
was not in any way involved in the editorial and peer- doi: 10.1016/j.arr.2023.102147
review process conducted for this paper, directly or
indirectly. Separately, other authors declared that they 8. Armstrong MJ, Okun MS. Diagnosis and treatment of
Parkinson disease: A review. JAMA. 2020;323(6):548-560.
have no known competing financial interests or personal
relationships that could have influenced the work doi: 10.1001/jama.2019.22360
reported in this paper. 9. Osetrova M, Tkachev A, Mair W, et al. Lipidome atlas of the

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