Three-dimensional midbrain organoids: a next-generation tool for Parkinson's disease modelling and drug discovery

Abstract

Parkinson's disease (PD), a progressive neurodegenerative disorder marked by dopaminergic (DA) neuron loss and Lewy body formation, lacks therapies to halt neurodegeneration. Current models, including 2D cultures and animal studies, fail to fully recapitulate human midbrain complexity, underscoring the need for advanced human-relevant disease modelling systems. Midbrain organoids (MOs), three-dimensional (3D) stem cell-derived neuronal structures mimicking midbrain architecture, have emerged as transformative tools for modelling PD. These organoids replicate key pathological hallmarks and enable disease mechanistic studies and drug screening for PD. Recent advances of research in MOs include genetic modelling of PD-linked mutations (e.g., LRRK2, GBA1, DNAJC6), optogenetics-assisted α-synuclein (α-syn) protein aggregation systems, and high-throughput drug testing platforms. MOs also show promise for cell replacement therapy, with successful integration and functional recovery in animal PD models. However, challenges such as batch variability, limited vascularization, incomplete neuronal maturation, and high costs hinder reproducibility and scalability. Future directions focus on integrating vascular networks, microglia co-cultures, automated workflows, and assembloid technologies to enhance pathophysiological relevance and translational potential in PD. By addressing these limitations, research in MOs could revolutionize PD research, offering critical insights into disease mechanisms and accelerating therapeutic discovery for PD patients.

1. Introduction

Parkinson's disease (PD) affected an estimated 11.9 million individuals worldwide in 2021, with projections suggesting a rise to 15.6 million in 2030, 20.4 million in 2040, and 25.2 million by 2050, driven primarily by global population aging and growth [1]. PD imposes a substantial dual burden in aging societies, with annual U.S. costs exceeding $50 billion from both direct healthcare expenses and indirect losses like reduced productivity and caregiver strain. Beyond economics, patients face social isolation and stigma, while families and healthcare systems grapple with caregiver burnout, rising hospitalizations, and disparities in specialized care access [2, 3]. Its pathological hallmark includes Lewy bodies formation and the gradual loss of dopamine (DA)-producing neurons in the substantia nigra pars compacta (SNpc) of the midbrain [4, 5]. As DA levels fall, patients develop characteristic PD motor symptoms, including resting tremor, rigidity, bradykinesia (slowness of movement) and postural instability, as well as a variety of non-motor features such as sleep disturbances, mood changes, and autonomic dysfunction [5].

Despite intensive research, there are currently no therapies that can halt or reverse the underlying neurodegeneration; available treatments (for example, levodopa and dopamine agonists) primarily aim to replenish DA or mimic its action and thus relieve patient symptoms [6, 7]. Deep brain stimulation (DBS), a surgical therapy used to manage motor symptoms and medication-induced complications, has also been applied in selected patients with early-stage PD [8]. However, while DBS can significantly improve motor function and quality of life, there is no conclusive evidence that it can alter the course of neurodegeneration or slow disease progression. Moreover, individual responses to these medications vary widely, and long-term use can lead to complications such as motor fluctuations and dyskinesias [9]. This clinical variability, together with PD's complex and multifactorial nature, continues to challenge the development of truly disease-modifying treatments. To address these challenges, researchers are leveraging advanced model systems, including cell-based assays, animal models, and patient-derived neuronal cultures.