Parkinson’s disease phenotypes in patient specific brain organoids are improved by HP-β-CD treatment

Abstract

The etiology of Parkinson's disease (PD) is only partially understood despite the fact that environmental causes, risk factors, and specific gene mutations are contributors to the disease. Biallelic mutations in the PTEN-induced putative kinase 1 (PINK1) gene involved in mitochondrial homeostasis, vesicle trafficking, and autophagy, are sufficient to cause PD. By comparing PD patient-derived cells, we show differences in their energetic profile, imbalanced proliferation, apoptosis, mitophagy, and a reduced differentiation efficiency to dopaminergic neurons compared to control cells. Using CRISPR/Cas9 gene editing, correction of a patient's point mutation ameliorated the metabolic properties and neuronal firing rates but without reversing the differentiation phenotype. However, treatment with 2-Hydroxypropyl-β-Cyclodextrin (HP-β-CD) increased the mitophagy capacity of neurons leading to an improved dopaminergic differentiation of patient specific neurons in midbrain organoids. In conclusion, we show that treatment with a repurposed compound is sufficient for restoring dopaminergic differentiation of PD patient-derived cells.

Patient-Derived Midbrain Organoids to Explore the Molecular Basis of Parkinson's Disease

“…Kim et al ( 77 ) showed that alpha-synuclein accumulation could be reduced in LRRK2 G2019S hMO through treatment with a LRRK2 kinase activity inhibitor (GSK2578215A), but also by knocking down the expression of TXNIP , which their study had identified as a central mediator of G2019S pathology. Jarazo et al ( 80 ) also found that treatment with the HP-ß-CD compound improved mDA neuronal differentiation in PINK1 and PRKN -mutated hMO, likely through increased mitophagy.…”

“…eEF2K, also known as Calmodulin-dependent protein Kinase III (CamKIII), is a crucial regulator of protein synthesis and synaptic plasticity, and is involved in a-syn mediated mitochondrial toxicity ( 79 ). Mutations in PINK1 , which encodes a mitochondrial kinase, have also been linked to reduced TH+ counts in hMO ( 80 ). Taken together, these studies suggest that hMO constitute a valid translational model to investigate the effects of different PD-associated mutations, as they reproduce elements of cellular pathology involving oxidative stress found in post-mortem tissue ( 81 ) (see Table 1 for summary).…”

Modeling Neurological Disorders in 3D Organoids Using Human-Derived Pluripotent Stem Cells

“…Therefore, these unique cell types can regulate tissue microenvironment by synthesizing various materials. Structural and functional alterations of the BMECs have been reported in several neurological disorders, such as stroke, traumatic brain injury, and neurodegenerative diseases (Liu et al, 2018a , b ; Jarazo et al, 2019 ). BMECs malfunction when they are removed from the brain microenvironment and cultured for extended periods of time.…”

“…Among these lines, most of them are familial PD with a single-gene mutation (Tran et al, 2020 ). For example, patient-derived iPSCs were prepared with PINK1 mutations and differentiated into neuroepithelial stem cells (NESCs), and later into neurons (Jarazo et al, 2019 ). This finding demonstrates that patient-derived NESCs can recapitulate PD-like phenotypes, such as reduction of differentiation efficiency, impaired mitophagy capacity, and increased cell death of dopaminergic neurons.…”

Midbrain Organoids: A New Tool to Investigate Parkinson’s Disease

“…In these approaches NPCs that received already some patterning toward the midbrain have been used. Both hMO models have been already used in other studies (Berger et al, 2018;Jan et al, 2018;Jarazo et al, 2019). Among the published hMO protocols, different approaches have been presented to estimate the number of mDANs that arise during the organoid development ( Table 2).…”