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EN1, and LMX1A, as well as other ventral and midbrain- established neural connections without tumor formation
specific markers. 145 (Figure 4C). Importantly, these grafts reversed motor
dysfunction in mice, highlighting the therapeutic potential
MBOs can simulate the development and function specific
to the human midbrain, particularly in the generation and of midbrain organoids for PD treatment.
regulation of dopaminergic neurons. As these organoids are 6. Conclusion and outlook
capable of autonomously producing and secreting dopamine,
they provide a powerful tool for studying PD and its This review highlights the potential of BOs as powerful
associated neurodegenerative mechanisms. By recapitulating tools for modeling human brain development and diseases.
key pathological features of PD, MBO models offer an However, the current variations in BO models across
experimental platform for studying disease progression studies underscore the need for standardized protocols in
and potential therapeutic targets, especially the study of model construction, experimental operations, and result
pathological mechanisms such as the abnormal accumulation evaluation. Establishing such standards will enhance
of α-synuclein, the degeneration of dopaminergic neurons, research comparability and reproducibility, driving the field
and the response of glial cells. Moreover, these functional toward more reliable outcomes. Future research should also
organoids aid in drug screening and the establishment of focus on refining specific directions, such as elucidating
neurological disease models, advancing the development developmental mechanisms, integrating advanced imaging
150
of PD-related treatments. and omics technologies to study pathophysiological
states, and developing high-throughput drug screening
5.3. Practical applications of organoids in PD platforms. Enhancing the long-term stability of BOs is
Organoid models have illuminated key pathological essential. Advanced bioreactors and ECM modifications can
mechanisms in PD, including α-synuclein aggregation, significantly improve BO viability by providing optimized
dopaminergic neuron loss, and neuroinflammation. culture conditions and supporting cell functions. These
Mutations in SNCA and LRRK2 genes, linked to PD, advancements will facilitate sustained BO development
enable the creation of organoid models using iPSCs from and enable more comprehensive studies. Furthermore,
patients. These models show reduced dopaminergic the clinical application of BO-based platforms holds great
neuron differentiation, altered mitochondrial morphology, promise, particularly in personalized medicine and drug
increased cell death, and elevated FOXA2 levels, which screening. By leveraging patient-derived iPSCs, BOs can
disrupt neuronal development. 151, 152 model individual disease states for precision diagnostics
and tailored therapies. Meanwhile, large-scale BO libraries
CRISPR/Cas9 technology has been used to model combined with automated screening technologies can
PD-related mutations in hESCs, revealing the impact of accelerate drug discovery and toxicity assessment. As
genetic alterations on neuronal function. Jarazo et al. 154 techniques continue to advance, BOs are poised to play a
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demonstrated the use of CRISPR/Cas9 in 3D organoids to transformative role in both research and clinical settings,
study PINK1 mutations, showing their effects on neuronal offering new hope for addressing neurological disorders.
differentiation and function (Figure 4A). HP-β-CD Meanwhile, ethical considerations in BO research need
was found to promote mitophagy and dopaminergic deeper exploration. Future work should focus on potential
neuron differentiation, mitigating PD phenotypes neural activity in BOs and its implications, addressing moral
caused by PINK1 mutations. Zagare et al. utilized and ethical boundaries. This will ensure responsible research
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midbrain organoids and single-cell RNA sequencing to practices and align BO technology with ethical standards.
study early developmental changes in PD. Their work
revealed significant neurodevelopmental alterations in Acknowledgments
LRRK2-p.Gly2019Ser mutant organoids compared to None.
healthy controls (Figure 4B). Another study showed
155
decreased TH-positive neurons and increased gliosis Funding
in PD-iPSC-derived organoids, highlighting the role
of inflammation in PD. 156 Organoids overexpressing This work was supported by the Research Initiation
GBA1 and SNCA demonstrated increased α-synuclein Project of Shanghai Fourth People’s Hospital Affiliated
aggregates, supporting the link between GBA1 mutations with Tongji University to the author FM.Y. (grant number:
and PD. LRRK2 G2019S mutations were associated with sykyqd11501).
elevated α-synuclein phosphorylation, implicating LRRK2
in dopaminergic neuron degeneration. 157,158 Zheng et al.’s Conflict of interest
research explored the therapeutic potential of hiPSC- Jie Zhang is an Editorial Board Member of this journal but
159
derived midbrain organoids (hMOs) in a PD mouse was not in any way involved in the editorial and peer-review
model. Transplanted hMOs survived, differentiated, and process conducted for this paper, directly or indirectly.

Volume 1 Issue 1 (2025) 13 doi: 10.36922/or.8261