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and mitochondrial stress responses, which are central in protecting cells oxidative stress and maintaining
to the pathogenesis of PD. Notably, since the PINK1/ mitochondrial function, both of which are essential for
Parkin mouse models do not exhibit predominant DA neuronal health, particularly in DA neurons. Mutations
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neuron loss or severe mitochondrial dysfunction, hMOs in PARK7, which are primarily associated with autosomal
further demonstrate their valuable role in exploring the recessive early-onset PD, result in a loss of DJ1 function,
underlying pathomechanisms of PINK1/Parkin in PD. In leading to increased oxidative damage, mitochondrial
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line with this, knocking out PINK1 and Parkin in human dysfunction, and DA neurodegeneration. Parfitt et al.
iPSC-derived midbrain-specific DA neurons significantly found that in a PD-associated hMO model with DJ1
impairs ionophore-induced mitophagy and reduces deficiency, impaired protein quality control pathways in
mitochondrial membrane potential, though it does not astrocytes lead to the accumulation of advanced glycation
affect neuronal differentiation. 41,42 This further underscores end products and α-synuclein aggregation, both of which
the importance of human iPSC-derived cells and organoid are hallmark features of PD pathology. The accumulation
models in studying the pathomechanisms of PINK1-related of these toxic proteins disrupts cellular homeostasis,
dysfunction. contributing to DA neuron degeneration. In addition, the
deficiency suppressed the clearance of misfolded proteins
2.4. DNAJC6 in astrocytes, further exacerbating neuronal toxicity. These
DNAJC6 encodes auxilin, a key protein involved in the findings suggest that DJ1 is not only critical for oxidative
recycling of clathrin-coated vesicles during endocytosis, stress and mitochondrial function but also plays a significant
a process essential for synaptic vesicle recycling and the role in maintaining cellular protein integrity. Thus, defects
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proper functioning of neurons. Loss-of-function mutations in DJ1 function can initiate a cascade of molecular events
in DNAJC6 lead to impaired synaptic vesicle recycling, leading to the degeneration of DA neurons, reinforcing
disrupting neurotransmitter release and contributing to DA its pivotal role in the pathogenesis of PD. Consistent with
neuronal dysfunction and degeneration, a characteristic of findings from organoid models, one group also utilized
early-onset or autosomal recessive juvenile parkinsonism iPSC-derived neurons carrying the homozygous c.192G>C
(AR-JP). 43,44 hMLOs with DNAJC6 loss-of-function mutation in DJ1 and identified a U1-dependent splicing
mutations have been proven to effectively recapitulate defect that led to a drastic reduction in DJ1 protein levels
several key disease phenotypes, including DA neuron and subsequent mitochondrial dysfunction. Targeting
degeneration, pathological α-synuclein aggregation, and this defective exon skipping with genetically engineered
increased intrinsic neuronal firing frequency. Furthermore, U1 small nuclear RNA successfully restored DJ1 protein
the disruption of DNAJC6-mediated endocytosis in these expression and mitochondrial function in both neuronal
models leads to significant defects in cellular processes critical precursor cells and differentiated neurons. Organoid
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for neuronal health, including impaired cellular trafficking models have been instrumental in elucidating DJ1’s role in
and organelle maintenance. Loss of DNAJC6 impairs the PD pathogenesis, providing valuable platforms for testing
function of the WNT-LIM homeobox transcription factor therapeutic interventions aimed at restoring DJ1 function
1 alpha (LMX1A) signaling cascade, resulting in reduced and mitigating neurodegeneration in PD.
expression of LMX1A, a key transcription factor essential
for DA differentiation. The reduced LMX1A expression 2.6. GBA
ultimately leads to the generation of vulnerable DA neurons GBA is a gene encoding the lysosomal enzyme
that exhibit pathological characteristics, such as α-synuclein β-glucocerebrosidase (GCase), which is essential for
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aggregation and altered cellular functions. Furthermore, breaking down glucocerebroside into glucose and ceramide.
one group generated an iPSC-derived midbrain DA GBA was initially identified for its association with
neuronal model using fibroblasts from patients with Gaucher disease; mutations in GBA were later linked to PD
pathogenic loss-of-function DNAJC6 mutations. Using through genetic studies. 50,51 As one of the most common
this model, they demonstrated that lentiviral DNAJC6 genetic risk factors for PD, GBA mutations (e.g., N370S
gene transfer successfully restored DNAJC6 expression and L444P) reduce enzyme activity, leading to lysosomal
and rescued clathrin-mediated endocytosis deficiency in dysfunction, the accumulation of glucocerebroside, and
midbrain DA neurons. These findings further underscore impaired autophagy. These defects promote the aggregation
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the complex molecular mechanisms underlying AR-JP of α-synuclein. In patient-specific GBA N370S hMOs,
and highlight the utility of hMOs as a valuable model for researchers found GBA-PD-related phenotypes, including
studying the disease. reduced GCase activity, impaired autophagy, mitochondrial
dysfunction, and a decline in both the number and
2.5. PD protein 7 complexity of DA neurons. Moreover, GBA-N370S-PD
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From PD protein 7 (DJ1), encoded by the PARK7 gene, hMOs exhibit DA neuron loss and an altered lipid profile,
is a multifunctional protein that plays a crucial role along with reduced sensitivity to changes in insulin

Volume 1 Issue 2 (2025) 5 doi: 10.36922/OR025040006