Table 1.
Genetic mutations and phenotypic outcomes in human midbrain-like organoids for Parkinson’s disease research
| Gene | Mutation | Phenotype | Reference |
|---|---|---|---|
| SNCA | SNCA triplication | Detergent-resistant, β-sheet-rich α-syn aggregates and spherically symmetrical Lewy body-like inclusions with eosinophilic cores form | Jo et al.80 |
| SNCA triplication | Elevated α-synuclein levels, age-dependent increases in α-synuclein aggregation, and selective loss of dopaminergic neurons | Mohamed et al.81 | |
| SNCA triplication | Accumulation of pathological αSyn, morphological resemblance to diverse stages of LB formation, and loss of DA neurons | Becerra-Calixto et al.82 | |
| SNCA triplication | α-synuclein aggregation, dopaminergic neuron loss, and astrosenescence with nuclear and chromatin alterations | Muwanigwa et al.83 | |
| LRRK2 |
G2019S LRRK2 mutation |
Increased α-synuclein aggregation, aberrant clearance, and gene expression profiles mimicking LRRK2-associated sporadic PD | Kim et al.31 |
|
G2019S LRRK2 mutation |
Decrease in number and complexity of mDANs, and increased FOXA2 expression | Smits et al.97 | |
|
G2019S LRRK2 mutation |
Untimely and incomplete differentiation with reduced cellular variability | Zagare et al.99 | |
| PINK1 | PINK1 knockout | CCCP/NH4Cl treatment reveals a PINK1- and Tom40-positive 720-kDa HMW complex in WT but not in PINK1 KO hMLOs | Eldeeb et al.109 |
| PINK1 knockout | Reduced growth rate and impaired DA neuronal differentiation | Brown et al.110 | |
| GBA1 |
L444P GBA1 mutation |
Significant reduction in GCase activity and TH+ neurons, increased insoluble α-synuclein, and phosphorylated α-synuclein | Baden et al.115 |
|
N370S GBA1 mutation |
Reduced GCase activity, impaired autophagy, mitochondrial dysfunction, altered lipid metabolism, fewer complex dopaminergic neurons, etc | Rosety et al.116 | |
| DNAJC6 | DNAJC6 knockout | Pathological α-synuclein aggregation, increased neuronal firing, mitochondrial and lysosomal dysfunctions, and neurodevelopmental defects | Wulansari et al.121 |
| PARKIN | PARKING knockout | Increased oxidative stress and enhanced dopaminergic neuron death upon differentiation | Ahfeldt et al.123 |
| ATP13A2 | ATP12A2 knockout | Elevated oxidative stress levels | Ahfeldt et al.123 |
| DJ-1 | DJ1 knockout | Elevated oxidative stress levels | Ahfeldt et al.123 |
| DJ1 knockout | AGE accumulation, increased α-synuclein phosphorylation, and protein aggregation | Morrone Parfitt et al.124 |