Microglia are the most important immune cells of the central nervous system (CNS). They constantly monitor brain tissue and respond to injuries, infections, or pathological changes. During the so-called neuroinflammation, they are activated, release pro-inflammatory substances such as TNFα, and, therefore, can influence other cells in the brain. In Parkinson’s disease, such neuroinflammation can contribute to the death of nerve cells, particularly dopaminergic neurons.

To investigate this, researchers are developing human midbrain organoids using induced pluripotent stem cells derived from the somatic cells of Parkinson’s patients. The focus is on cells of the ventral midbrain, where the dopaminergic neurons of the substantia nigra are located. These cells are particularly affected by Parkinson’s disease and die off as the disease progresses, leading to typical symptoms such as movement disorders. Over several weeks, the organoids develop and form various cell types of the midbrain, including dopaminergic neurons, astrocytes, and oligodendrocytes. Then, microglia carrying a mutation typical of Parkinson’s disease (LRRK2-G2019S) are added to the midbrain organoids. This allows scientists to observe that these mutated microglia exhibit an increased tendency toward inflammation and release higher levels of the inflammatory mediator TNFα. At the same time, the microglia alter their metabolism to sustain this activity. The increased inflammation leads to the targeted death of dopaminergic neurons in the organoids—a key hallmark of Parkinson’s disease.

A research team treated the organoids with the active ingredient oxamic acid, for example, which inhibited the metabolic enzyme glycolysis in the microglia. As a result, the inflammatory response decreased, and more dopaminergic neurons survived in the organoids. (x) However, other active ingredients such as ambroxol, levodopa, and others—including new ones—were also tested.

Original publication:
Zagare A, Jarazo J, Schwamborn J. Brain organoids in Parkinson’s disease drug development: Human-specific models for translational discovery. Drug Discov Today. July 17, 2026:104742. doi: 10.1016/j.drudis.2026.104742. Epub ahead of print. PMID: 42468620.

Additional references:
(x) Kurniawan H, et al. The Parkinson’s disease-associated LRRK2-G2019S variant restricts serine metabolism, leading to microglial inflammation and dopaminergic neuron degeneration. J Neuroinflammation. 2025;22:244.