Page 38 - AN-4-4

Advanced Neurology Lipid metabolism and Parkinson’s disease

1. Introduction disturbances disrupt energy metabolism, elevate oxidative
stress, and promote neuroinflammation, ultimately
Parkinson’s disease (PD), the second most prevalent exacerbating progressive neuronal damage. Dopaminergic
neurodegenerative disease worldwide, affects more than neurons, in particular, are extremely sensitive to abnormal
10 million individuals with a male-to-female prevalence lipid metabolism due to their high metabolic demands
ratio of approximately 2:1. The pathological hallmarks and strong dependence on FA β-oxidation. Moreover,
1-3
include the progressive degeneration of dopaminergic synaptic function has stringent requirements for the
neurons in the substantia nigra pars compacta (SNc) and composition and metabolic dynamics of membrane lipids.
the formation of Lewy bodies—intracellular inclusions
primarily composed of misfolded α-synuclein (α-Syn). Consequently, lipid dyshomeostasis directly induces
4,5
These pathologic changes contribute to both motor synaptic dysfunction, leading to reduced dopamine release
symptoms (e.g., resting tremor and bradykinesia) and non- and synapse loss.
motor manifestations (e.g., hyposmia, sleep disturbances, This review provides a systematic examination of
and cognitive impairment) with symptom severity the multifaceted roles of dysregulated lipid metabolism
progressing alongside neuronal loss, severely impacting in PD. It comprehensively analyzes three key aspects:
patients’ quality of life. While α-Syn aggregation remains the effects of lipid homeostasis imbalance on neuronal
6,7
a central event in PD pathogenesis, growing evidence functions, the mechanisms underlying dysregulated lipid–
implicates mitochondrial dysfunction, oxidative stress, organelle interactions, and the critical contribution of lipid
and inflammatory responses as synergistic drivers, with metabolism abnormalities to PD pathogenesis. Through
lipid metabolism dysregulation increasingly recognized as the integrated analysis, the review elucidates the pivotal
a unifying mechanism linking these processes. 8 role of dysregulated lipid metabolism in PD progression
Lipids, including cholesterol, fatty acids (FAs), and evaluates its potential as a therapeutic target for
glycerophospholipids, and sphingolipids, serve as critical disease intervention.
structural components and key regulators of neuronal 2. Lipid homeostasis
function. The human brain, composed of approximately
9
50% lipids by dry weight, is the most lipid-rich organ after 2.1. Lipid homeostasis in the brain
adipose tissue. Notably, lipid homeostasis in the brain Lipid homeostasis in the brain refers to the dynamic
10
is fundamental to key physiological processes essential balance of lipid synthesis, metabolism, transport, and
for maintaining neuronal cell membrane integrity, distribution. As fundamental structural components
30
neural signaling, synaptic function, and inflammatory of neuronal membranes and key regulators of cellular
modulation. 11-17 In PD, disruptions in lipid homeostasis function, lipids are tightly associated with the etiology,
not only lead to decreased cell membrane fluidity, impaired progression, and severity of neurodegenerative diseases. 31
synaptic function, and neuronal death, but also amplify
PD pathogenesis by disrupting mitochondrial function Phospholipids, a major class of brain lipids, are essential
and promoting α-Syn aggregation. 10,18-21 Furthermore, for maintaining neuronal membrane structure and
dysregulated lipid metabolism activates microglia, driving synaptic integrity. Disruptions in phospholipid balance
excessive neuroinflammation and creating a vicious reduce membrane fluidity, impair synaptic function, and
cycle of neuronal damage. 22-25 Therefore, elucidating the accelerate neuronal death. Beyond membrane structure,
10
mechanisms of lipid dysregulation in PD is important lipids are vital to mitochondrial function, serving as key
for unravelling the disease’s etiology, identifying early constituents of mitochondrial membranes. Dysregulated
diagnostic markers, and developing novel therapeutic lipid homeostasis directly impairs mitochondrial
strategies. energy metabolism (e.g., adenosine triphosphate [ATP]
production) and diminishes antioxidant capacity,
In PD, lipid metabolism dysregulation manifests 32
through multiple organelle dysfunctions and interplay exacerbating energy deficits in neurons.
imbalances. 16,26,27 For example, the dysregulation of Notably, progressive degeneration of nigrostriatal
mitochondria–lipid droplet (LD) interactions results dopaminergic neurons characterizes the central
in both LD accumulation and mitochondrial lipid pathological feature of PD. Specific lipids, including
deficiency. Similarly, impaired phospholipid exchange sphingolipids, modulate PD pathogenesis by altering α-Syn
28
at mitochondria-associated endoplasmic reticulum conformation and aggregation rates. Under conditions of
(ER) membranes affects cardiolipin (CL) biosynthesis, lipid dyshomeostasis, aberrant lipids (e.g., oxidized FAs)
while lysosomal dysfunction induces abnormal lipid promote the formation of toxic α-Syn aggregates, further
degradation. 26,29 Collectively, organelle-mediated lipid damaging neurons. Brain lipids, particularly unsaturated
22

Volume 4 Issue 4 (2025) 32 doi: 10.36922/AN025320086