A promising drug in the fight against Parkinson's disease

Scientists are using cutting-edge organoid technology to uncover the causes of Parkinson's and accelerate the development of new treatments.

Study: Human midbrain organoids: a powerful tool for advanced Parkinson's disease modeling and therapeutic discovery. Image source: mi_viri/Shutterstock.com

In a recently published review in the npj Parkinson's diseasea group of authors examined the use of human midbrain organoids (mini 3D organ models) in Parkinson's disease (PD) (movement disorder) research, drug screening, and therapy, highlighting challenges and optimization strategies.

background

PD is a common neurodegenerative disease affecting over 6.1 million people worldwide. It is characterized by motor symptoms such as tremor, bradykinesia (slow movement) and rigidity, as well as non-motor problems such as depression and cognitive decline.

Loss of dopaminergic neurons in the midbrain and the presence of Lewy bodies composed of abnormal α-synuclein protein are hallmarks of Parkinson's disease. Current research tools, including postmortem brain tissue, animal models, and cell cultures, have limitations.

Further research is needed to develop better, human-relevant models to understand the mechanisms of Parkinson's disease and improve treatment options.

Midbrain organoids and PD

Over the last decade, the rise of three-dimensional (3D) organoid technology has revolutionized stem cell research.

Organoids, which are miniature in vitro 3D cellular structures derived from induced pluripotent stem cells (iPSCs) or isolated progenitor cells, mimic many aspects of human organs.

This technology has been particularly useful in modeling various parts of the brain, including the forebrain, midbrain and hippocampus. Brain organoids play an important role in the study of neurological development and the recapitulation of human diseases such as Parkinson's disease.

Development of human midbrain organoids (hMLOs)

hMLOs represent a significant advance in disease modeling, particularly Parkinson's disease. While markers of midbrain dopaminergic (mDA) neurons have been found in general brain organoids, their proportions tend to be small and inconsistent.

To address this problem, scientists have developed more targeted protocols for generating mDA neurons in hMLOs. The process involves two phases: floor plate induction and organoid development, in which iPSCs are differentiated into 3D structures with midbrain-specific markers.

One of the first successful protocols for generating hMLOs was developed, converting a 2D differentiation method into a 3D suspension approach. Their results showed high efficiency in the production of mDA precursors and mature dopaminergic neurons.

Further advances over the next few years led to protocols that enabled long-term preservation and maturation of these organoids.

As a result, these hMLOs resemble essential features of the midbrain, including layers containing progressively maturing neurons and neuromelanin granules typically found in the human substantia nigra.

Applications in PD research

PD model making

Organoids are widely used to model neurodegenerative diseases, including Alzheimer's disease, Huntington's disease, and Parkinson's disease. Traditional Parkinson's models such as animal models and 2D cell cultures have limitations. Although postmortem brain tissues from Parkinson's patients provide valuable insights, they are difficult to obtain and may not always represent living conditions.

Animal models also face problems related to species-specific differences in disease mechanisms.

The advent of hMLOs has addressed some of these challenges. hMLOs can be created from patient-derived iPSCs or through gene editing techniques, allowing researchers to study genetic mutations associated with Parkinson's disease.

These organoids reproduce key features of Parkinson's disease, such as: B. α-synuclein aggregation, degeneration of dopaminergic neurons and other pathological changes.

Prediction of PD toxicity

Toxin-based Parkinson's models have been developed using hMLOs to study how environmental toxins contribute to the disease. Two prominent examples are the use of the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA).

MPTP is a reliable dopaminergic neurotoxin that has been used in animal models to induce PD-like symptoms. By treating hMLOs with MPTP, researchers observed selective degeneration of mDA neurons, providing a valuable model for studying Parkinson's-related neurotoxicity in vitro.

Similarly, 6-OHDA treatment resulted in reduced numbers of dopaminergic neurons and fragmented neurites in organoids, providing another tool for PD modeling.

In addition, oxidative stress plays an important role in the progression of Parkinson's disease, and hMLOs have been used to evaluate the effects of various oxidative stress-inducing compounds on dopaminergic neurons. These models have proven effective in simulating neurodegenerative processes associated with Parkinson's disease, thus enabling research into possible therapeutic interventions.

Developing treatments for Parkinson's disease

The therapeutic potential of hMLOs is immense. One promising application is the generation of neural stem cells (NSCs) from midbrain organoids. These NSCs can differentiate into mDA neurons, which are crucial for Parkinson's treatment.

When transplanted into animal models of Parkinson's disease, these cells demonstrated the ability to integrate into neuronal circuits, restore motor function, and even prevent tumor formation.

In addition to cell-based therapies, hMLOs have also played an important role in drug screening. Traditional 2D cell cultures often cannot predict how drugs will behave in humans, but hMLOs, with their complex 3D structure, offer a more reliable platform for testing drug effectiveness.

For example, studies have shown that certain compounds can reduce α-synuclein accumulation in hMLOs with leucine-rich repeat kinase 2 (LRRK2) mutations, highlighting their potential for drug development in Parkinson's disease.

Conclusions

In conclusion, Parkinson's is a difficult neurodegenerative disease due to its progressive and irreversible nature. Early diagnosis remains difficult because there are no reliable markers and brain biopsies offer limited benefits.

Furthermore, there are no disease-modifying drugs to prevent or reverse the disease, in part because the underlying mechanisms remain unclear. Established animal models encounter scalability and ethical limitations in high-throughput drug testing.

iPSCs have improved disease modeling, but the advent of organoids has created a more advanced platform for studying Parkinson's disease and opened new opportunities for disease progression simulation, drug screening, and therapeutic intervention.