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neurites, which are implicated in neurotoxicity through and Parkin help study familial PD but often do not fully
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mechanisms such as disrupted proteostasis, mitochondrial represent sporadic cases. In addition, transgenic mouse
dysfunction, and synaptic impairments. These pathological models generally lack the gradual onset and α-synuclein
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changes not only compromise neuronal survival but also aggregation seen in human PD, making them less ideal for
contribute to the widespread neurodegenerative processes studying disease progression. They do not fully replicate
observed in PD. Mitochondrial dysfunction plays a critical the complexity of human PD, especially in terms of the
role in PD pathogenesis, particularly in cases associated gradual onset and progression of the disease. For example,
with mutations in PINK1 and Parkin. These mutations PINK1 and Parkin mutant mice often exhibit early-onset
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impair mitochondrial quality control mechanisms, neurodegeneration, which does not mirror the gradual
leading to the accumulation of damaged mitochondria, progression observed in human PD. In addition, these
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increased oxidative stress, and heightened susceptibility mouse models often lack the same degree of α-synuclein
to neurodegeneration. Neuroinflammation is another key aggregation, a hallmark of PD pathology, limiting their
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contributor to PD pathology. Chronic neuroinflammation, ability to model this key aspect of the disease. Similarly,
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characterized by the sustained activation of microglia LRRK2-related animal models provide insights into genetic
and astrocytes, leads to the release of proinflammatory factors but fail to encompass environmental influences
cytokines and reactive oxygen species, exacerbating and age-related degeneration typical of human PD.
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neuronal damage and promoting the progression of PD. Moreover, these models do not effectively reproduce the
Disruptions in lysosomal function and autophagy pathways involvement of non-DA systems and broader factors, such
further contribute to PD pathology. Mutations in genes as neuroinflammation, that contribute to the full spectrum
such as GBA1 and LRRK2 impair lysosomal degradation of PD pathology. Consequently, while valuable for basic
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and autophagy, leading to the accumulation of toxic protein research, these animal models have significant limitations
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aggregates and increased cellular stress. The inability to in accurately modeling the human form of PD.
clear misfolded α-synuclein exacerbates neurotoxicity, The rapid advancement of stem cell technology has led
reinforcing a vicious cycle of protein accumulation and to the emergence of organoids as a transformative tool in
neuronal dysfunction. Emerging evidence suggests that gut- biomedical research. Organoids are three-dimensional
brain axis dysfunction also plays a role in PD pathogenesis. (3D), miniaturized versions of organs that are created
The bidirectional communication between the gut and the from stem cells and exhibit some of the key functions
central nervous system may influence neuroinflammatory and structures of the original organ. They are derived by
and neurodegenerative processes, with some studies differentiating stem cells into specific tissue types in a
suggesting that α-synuclein pathology may originate in the laboratory setting, and they can replicate the architecture
gut and propagate to the brain through the vagus nerve. and functionality of organs such as the brain, liver, and
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While significant progress has been made in identifying kidneys. The first brain organoids were generated in 2009,
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individual genetic mutations and environmental risk which shows that adult intestinal stem cells can form 3D
factors, the precise mechanisms by which these elements intestinal organoids in Matrigel. Since then, the field of
interact to drive PD pathogenesis remain incompletely organoid research has expanded rapidly, particularly in
understood, highlighting the necessity for continued the study of neurodegenerative diseases, like PD and
research to elucidate these interactions. Alzheimer’s disease, cancer, and organ development,
Research in PD relies on various models, each with providing valuable insights for disease modeling and
unique advantages and limitations. Human brain tissue drug testing. In PD research, human midbrain organoids
from post-mortem donations, biopsies, or patient-derived (hMOs) are frequently used because they closely mimic
induced pluripotent stem cells (iPSCs) provides valuable the structure and cellular composition of the midbrain,
insights into disease mechanisms within DA neurons, which is the region most affected by the disease.
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offering greater relevance than traditional animal models Unlike conventional two-dimensional (2D) cell cultures,
or cell cultures. However, challenges such as sample which often have a limited range of cell types and fail to
variability, ethical concerns, and difficulty in accessing capture the complex interactions within the tissue, hMOs
early disease stages limit their utility. Animal models, feature a 3D structure that simulates the brain’s natural
including toxin-induced and genetic models, are widely environment, containing a variety of cell types, such as
used but have inherent limitations. Toxin-based models DA neurons and glial cells, allowing the examination of
like 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine cell-cell interactions and neuronal networks. In addition,
(MPTP) and 6-hydroxydopamine (6-OHDA) replicate 3D organoids can be maintained for extended periods,
DA neuron loss and motor deficits but fail to mimic the enabling researchers to study key pathological mechanisms
progressive and multifactorial nature of PD. Genetic in the context of both aging and early-onset PD. In this
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models incorporating mutations in SNCA, LRRK2, PINK1, review, we first provide an overview of organoid models in

Volume 1 Issue 2 (2025) 2 doi: 10.36922/OR025040006