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α-synuclein proto-fibrils (PFFs). Using PFF-treated HMOs, LRRK2 G2019S mutation, Zhou et al. observed significant
researchers discovered that Tilorone effectively inhibits electrophysiological alterations in disease-associated COs
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α-synuclein PFF-induced neuronal toxicity. Overall, compared to healthy controls. These changes included
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hMOs carrying SNCA triplications provide a valuable reduced neuronal network communication, slowed neuronal
platform for studying α-synuclein aggregation, DA neuron oscillations, and increased coupling of delta and theta phases
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degeneration, and the mechanisms driving PD progression. to gamma oscillation amplitudes. In addition to neuronal
These models not only enable the exploration of disease cells in organoid models, human iPSC-derived microglia
mechanisms but also offer a robust system for evaluating carrying the LRRK2 G2019S mutation also replicate
potential therapeutic interventions targeting α-synuclein key aspects of the transcriptional signature observed in
pathology and its downstream neurotoxic effects. midbrain microglia from individuals with idiopathic PD.
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These studies highlight that organoid models for LRRK2
2.2. LRRK2 effectively replicate the pathological features of PD and serve
The LRRK2 gene encodes a kinase that regulates protein as valuable models for exploring the disease mechanisms
trafficking and inflammatory pathways, playing a significant underlying LRRK2-induced neuronal toxicity.
role in PD pathogenesis. Since its identification in 2004 as
a key genetic factor for PD, several pathogenic mutations – 2.3. PINK1 and Parkin
including Asn1437His, Arg1441Cys/Gly/His, Tyr1699Cys, PINK1 and Parkin are crucial genes implicated in autosomal
Ile2020Thr, and Gly2019Ser – have been associated with recessive PD, playing fundamental roles in mitochondrial
disease development. Among these, the G2019S missense quality control and mitophagy. 34,35 Mutations in PINK1,
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mutation is the most common genetic contributor to both such as E283A and R342H, and in Parkin, such as C418Y,
familial and sporadic PD, leading to overactive kinase activity result in mitochondrial dysfunction and impaired
that disrupts normal cellular processes. This dysfunction mitophagy, ultimately leading to the degeneration of DA
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is linked to various pathological characteristics of PD, such neurons. PINK1, a mitochondrial kinase, accumulates on
as mitochondrial impairment, compromised autophagy, the outer membrane (TOM) of damaged mitochondria
and abnormal protein aggregation, including α-synuclein. and recruits the E3 ligase Parkin. 34,35 Parkin ubiquitinates
Studies confirm that hMOs derived from PD patients mitochondrial proteins, targeting them for autophagy,
carrying the LRRK2 G2019S mutation exhibit PD-related which removes defective mitochondria to maintain
phenotypes, including reduced complexity, increased quality, prevent dysfunction, and protect DA neurons
α-synuclein aggregation, and its impaired clearance, from PD-related damage. 36,37 A human isogenic organoid
as well as a decrease in the number of DA neurons. 17,28 model with PINK1 deficiency revealed that while overall
Zagare et al. used single-cell transcriptome datasets to neuronal differentiation remained comparable between
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compare the shared cellular identities between healthy PINK1-deficient organoids and their isogenic controls, the
hMOs and human embryonic midbrain tissue, as well as deficient organoids exhibited specific impairments in DA
between healthy midbrain organoids and LRRK2-G2019S neurogenesis. This finding underscores PINK1’s essential
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isogenic hMOs. Their analysis demonstrates that hMOs role in DA neuron development and suggests that its loss
accurately replicate human midbrain development and may contribute to early neurodevelopmental vulnerabilities
capture a gene expression profile associated with LRRK2- in PD. In addition, studies using hMOs have highlighted
G2019S mutations, which may underline the phenotypes PINK1’s role in mitochondrial stress responses. Eldeeb
related to LRRK2 mutations. Further investigations into et al. demonstrated that PINK1 is necessary for stabilizing
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the molecular mechanisms of LRRK2 G2019S mutations translocase of TOM and translocase of the inner membrane
have revealed their impact on dopamine metabolism 23 complexes under mitochondrial stress conditions,
and neuronal survival. Zhou et al. demonstrated that such as carbonyl cyanide m-chlorophenylhydrazone and
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LRRK2 mutations upregulate tyrosine hydroxylase (TH) ammonium chloride exposure. PD-associated PINK1
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expression and dopamine levels in the early stages of mutations disrupt the interaction between TOM20
PD, ultimately leading to DA neuron degeneration. In and PINK1, preventing the formation of the super
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addition, Kim et al. identified thioredoxin-interacting complex, which links mitochondrial stressors to PINK1
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protein (TXNIP) as a key mediator that regulates LRRK2 accumulation in midbrain organoids. Beyond PINK1’s
G2019S pathological phenotypes in hMOs. TXNIP role, organoid models derived from iPSCs of PD patients
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was previously found to be a risk factor for PD that with Parkin mutations have provided additional insights
significantly accelerates the accumulation of α-synuclein. into disease pathology. These hMOs display abnormal
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Dysregulation of TXNIP may exacerbate PD pathogenesis astrocytic reactivity compared to age- and sex-matched
in LRRK2 G2019S sporadic PD within a three-dimensional controls, suggesting that Parkin mutations may influence
cellular environment. Moreover, using cerebral organoids glial function in PD. Taken together, these models reveal
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(COs) derived from fibroblasts of individuals carrying the critical defects in DA neurogenesis, astrocytic reactivity,
Volume 1 Issue 2 (2025) 4 doi: 10.36922/OR025040006