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cell membrane permeability, leading to increased Ca² the brain. In addition, dopamine agonists and monoamine
+
influx and the production of excessive reactive oxygen oxidase B inhibitors are also widely used, aiming to prolong
species, which activate astrocytes and trigger inflammatory the action of dopamine in the body. When drug treatment
responses. As Ca² accumulates in the mitochondria, the is ineffective or the disease progresses to a certain stage,
+
disruption of oxidative phosphorylation further promotes surgical treatments such as deep brain stimulation (DBS)
the aggregation of α-synuclein, forming toxic oligomers can serve as an effective supplement to improve patients’
or fibrillary structures. These α-synuclein deposits not motor symptoms. Although DBS has achieved certain
only directly damage neurons but also disrupt the integrity successes clinically, being a symptom management method,
of the BBB, further promoting inflammatory responses it cannot stop the degeneration of neurons or reverse the
and neuronal damage. Microglia play a significant role progression of the disease.
in the progression of PD. The dysfunction of microglia,
combined with the imbalance of sphingolipid metabolism, 5.2. Organoid strategies for PD
activates the inflammasomes, exacerbating the degree of 5.2.1. Traditional models and organoids in PD
neuroinflammation. This inflammatory response not only research
accelerates the aggregation and spread of α-synuclein but While neurospheres and spheroids have been foundational
also intensifies neuronal death, thereby advancing the in neuroscience, BOs represent significant advancements
disease. 131,132
for PD research. Neurospheres, primarily composed of
5.1.3. Genetic research in PD NSCs, are limited to short-term studies of proliferation
and differentiation, lacking the complexity needed to
The pathological processes and progression of PD are model neurodegenerative pathologies. Similarly, spheroids,
closely associated with multiple genetic and environmental typically derived from tumor cells or fibroblasts, focus on
factors. Research indicates that numerous risk genes related oncological applications and do not replicate neuronal-glial
to PD play a significant role in the onset and development diversity or brain developmental processes. In contrast,
of the disease. For instance, single-gene mutations BOs generate diverse cell types critical for PD studies,
130
in SNCA, PARK2, PINK2, and LRRK2 genes have been including excitatory/inhibitory neurons, astrocytes,
identified as being associated with PD, and the causes of and oligodendrocytes, while accurately recapitulating
some PD patients can be traced back to mutations in these brain development and disease progression. Their
genes. Although a minority of PD patients are caused by reproducible cellular and transcriptional profiles, despite
these major single-gene mutations, findings from genome- variability across iPSC lines, enable robust modeling of
wide association studies in recent years have shown that PD neurodevelopmental and degenerative mechanisms. In
has a polygenic inheritance pattern. Research over the past addition, BOs form functional neural networks that mature
25 years has identified more than 100 genetic loci associated over time, simulating in vivo dynamics – a feature absent
with PD risk. 131,132 While each of these loci may have a in simpler 3D models. By integrating tissue complexity,
small individual effect on PD risk, their combined action pathological detail, and long-term functionality, BOs
in PD onset is considerable. This polygenic inheritance provide a transformative platform for investigating PD
pattern provides a more comprehensive perspective for etiology and therapeutic strategies.
understanding the genetic background of PD, indicating
that PD is not a disease driven by a single gene but rather 5.2.2. Parkinson’s organoid model strategies
the result of complex interactions between multiple genes iPSCs are generated from PD patient-derived somatic
and environmental factors.
cells (e.g., fibroblasts) using reprogramming factors
5.1.4. Principles of PD treatment (Sox2, Oct3/4, c-myc, Klf4), retaining the donor’s genetic
background for studying disease-specific mutations. 125,134,135
Patients with PD exhibit typical motor symptoms such as These iPSCs are then differentiated into dopaminergic
tremors, rigidity, bradykinesia, and postural instability. neurons relevant to PD through dual-SMAD inhibition
In addition, PD is also accompanied by many non- and signaling pathways such as sonic hedgehog (SHH) and
motor symptoms, such as sleep disturbances, hyposmia, FGF8b, exhibiting key PD phenotypes such as α-synuclein
autonomic dysfunction, and impairments in cognitive and accumulation and mitochondrial dysfunction. 136-139
mental functions. 133 Midbrain-like organoids are subsequently developed by
At present, the main treatment for PD is medication, culturing iPSCs in a 3D matrix (e.g., Matrigel), promoting
which typically works by supplementing dopamine or self-organization into neural tissues with functional
inhibiting acetylcholine to alleviate symptoms. Levodopa neural networks and time-dependent maturation. 140-142
(L-Dopa) is the most commonly used drug, which alleviates These PD-specific organoids recapitulate pathogenic
motor symptoms by increasing the level of dopamine in features like lysosomal dysfunction and are used to study

Volume 1 Issue 1 (2025) 11 doi: 10.36922/or.8261