Table 1.

Studies using 3D cultures and COs to model other neurodegenerative diseases

Disease	Origin/Cell line	Model	Pathology	Reference
Parkinson's Disease (PD)	Healthy hNESCs	3D microfluidic bioreactor - matrigel embedded hNESCs with medium flow on one/either side of chamber	Mature neurons with bipolar morphology, larger neurites, branching, interconnectivity and synchronized electrical activity. Only 19% of neurons express tyrosine hydroxylase indicative of dopaminergic neurons	Moreno et al, 2015 [183]
	Healthy hPSCs	Seeding of dissociated 2D hPSCs grown into mebiol gel	Development of floorplate-derived substantia nigra-specific midbrain dopaminergic neurons with high tyrosine hydroxylase levels. Electrophysiologically active	Adil et al, 2017 [184]
	hNESCs with LRRK2 G2019S variant	Midbrain organoids	Clusters of dopaminergic neurons with high neurite myelination. Presence of astrocytes and oligodendrocytes	Monzel et al, 2017 [185]
	hiPSCs with LRRK2 G2019S variant	Neuroepithelial spheres	Transcriptomic profiles show alterations in synaptic transmission (synaptic vesicle trafficking), axon guidance, toll-like receptor signaling pathway and TGF-β signaling pathway	Son et al, 2017 [186]
	PD hiPSCs with Q456X and I368N variants in PINK1	Cerebral organoids	Decrease in dopaminergic neurons, neuronal loss. Decrease in differentiation efficiency with increase in proliferation. Altered electrical activity with decrease in mitophagy. HP-β-CD treatment increase differentiation efficiency	Jarazo et al, 2019 [187]
	hiPSCs with LRRK2 G2019S variant	Midbrain organoids	α-synuclein aggregate pathology with defective clearance. Increase in TXNIP levels involved in LRRK2-associated PD	Kim et al, 2019 [188]
	hiPSCs derived midbrain floor plate NPCs with LRRK2 G2019S variant	Midbrain organoids	Decrease in the number and complexity of dopaminergic neurons. Increase in FOXA2 levels indicating neurodevelopmental defect	Smits et al, 2019 [189]
	hiPSCs from two idiopathic PD patients	Midbrain organoids	Defective neurodevelopment with dopaminergic neuronal loss and reduction in organoid growth. Low levels of midbrain floorplate progenitors FOXA2 and LMX1A and high levels of PTX3 gene involved in dopaminergic neurodevelopment and survival	Chlebanowska et al, 2020 [190]
	Single cell dissociated from hESCs	Midbrain organoids	Presence of dopaminergic neurons and glial cells with dopamine and neuromelanin-like granules. MPTP treatment leads to astrocyte mediated dopaminergic neuronal loss. electrophysiological activity	Kwak et al,2020 [191]
Frontotemporal Dementia (FTD)	hiPSCs with tau P301L and tau P301L:∆p35KI	Cerebral organoids	Higher p25/p35 protein ratios. Decrease in p25, pTau-T181, S202 and total tau in P301L∆ p35KI COs. Inhibition of p25/Cdk5 reduces tau phosphorylation and pathology and increases synaptic density	Seo et al, 2017 [59]
	hiPSCs with R406W variant	Cortical neurons from dissociated organoids	Tau hyperphosphorylation and mislocalization to dendrites. Mitochondrial destabilization and axonal transport disruption. Decrease in phosphorylation by GSK3β, Rho-associated protein kinase (RhoK) and protein kinase A (PKA) at T181, S404, S409 sites	Nakamura et al, 2019 [192]
Amyotropic Lateral Sclerosis (ALS) and Motor Neuron Disease (MND)	Human chorion derived mesenchymal stem cells	3D culture - cross-linked electrospun gelatin scaffolds	Shh and RA induction upregulate motor neuron proteins such as islet-1, choline acetyl transdferase, nestin, NEFH and transcription factor Hb-9 responsible for neuronal differentiation. Decrease in NEFH after a week	Faghihi et al, 2016 [193]
	hiPSCs derived spinal motor neuron spheroid	Microdevice-chamber for MN spheroid, axon fascicle microchannel and chamber for axon terminals	Strong electrical activity and axonal staining. Hydrogen peroxide treatment mimics neurodegeneration resulting in physical changes of the axon fascicle such as reduced/damaged microtubules, changes in directionality, texture, and elasticity	Kawada et al, 2017 [194]
	NSCs and skeletal myoblast from sALS hiPSCs	Microdevice-MN spheroid, muscle tissue, and neurite elongation chamber	Low muscle contractions with increase in motor neuron degradation and apoptosis. Bosutinib and rapamycin treatment leads to increase in autophagy and TDP-43 degradation	Osaki et al, 2018 [195]
	Isogenic hiPSCs with and without H517D variant in FUS gene	Nerve organoid	FUS nerve organoid show abnormal axon morphology and aberrant axon branching with increase in Fos-B mRNA levels (binding target of FUS). Suppression of Fos-B using siRNA rescues FUS-ALS pathology	Akiyama et al, 2019 [196]
Huntingtion Disease (HD)	HD hiPSCs with Q21, Q28, Q33, Q60, Q60, Q109, Q180 CAG repeats	Cerebral organoids	Abnormal neural development - defects in neuronal maturation and organization; CAG expansion-dependant cortical and striatal specification defects; neuronal migration and differentiation defects	Conforti et al, 2017 [197]

Note: COs: Cerebral organoids; hNESCs: Human neuroepithelial stem cells; hPSCs: Human pluripotent stem cells; LRRK2: Leucine-rich repeat kinase 2; TGF-β: Transforming growth factor beta; PINK1: PTEN-induced putative kinase 1; HP-β-CD: 2-Hydroxypropyl-beta-cyclodextrin; TXNIP: Thioredoxin Interacting Protein; NPCs: Neural Progenitor Cells; FOXA2: Forkhead box protein A2; LMX1A: LIM homeobox transcription factor 1; PTX3: Pentraxin 3; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; CDK5: Cyclin Dependent Kinase 5; Shh: Sonic hedgehog; RA: Retinoic Acid; NEFH: Neurofilament Heavy polypeptide; MN: Motor Neuron; NSCs: Neural Stem Cells; FUS: Fused in Sarcoma