An innovative 3D model to study Parkinson’s disease and test new therapies

It is an organoid that reproduces the midbrain, the brain area most affected by the disease, derived from stem cells taken from patients with mutations in the GBA1 gene, one of the main genetic risk factors.

The study—developed by researchers coordinated by the neurologists of Policlinico di Milano, Emanuele Frattini and Alessio Di Fonzo, and published in the journal Brain—allows a deeper understanding of the disease mechanisms and the testing of new drugs, paving the way for increasingly targeted therapies.

Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s. Currently, it is the fastest-growing neurological condition worldwide: in Italy alone, it affects about 300,000 people, and it is estimated that in the next 30 years, the number of cases could double. It manifests in different forms, all characterized by the degeneration of neurons in the midbrain, a deep brain region responsible for producing dopamine, a neurotransmitter essential for many functions, including motor control. Dopamine deficiency causes symptoms such as slowed movements, tremors, stiffness, and other neurological alterations.

A key role in disease progression is played by the accumulation of the protein α-synuclein, which forms aggregates known as Lewy bodies, whose dysfunction compromises neuronal function. Moreover, recent studies have shown that some forms of Parkinson’s are associated with genetic mutations that alter the mechanisms of cellular molecule degradation and recycling. In particular, over 10% of patients carry mutations in the GBA1 gene, which encodes the enzyme β-glucocerebrosidase (GCase). When this enzyme is altered, it cannot properly degrade the lipid glucosylceramide, whose accumulation promotes α-synuclein aggregation and contributes to neuronal degeneration. However, the lack of reliable experimental models has so far made it difficult to understand the link between mutated glucocerebrosidase and the disease.

To address this need, an innovative protocol has been developed that recreates in the laboratory the environment and the genetic alterations in which the disease develops. This was achieved thanks to the coordinated work of specialists in Neurology, led by Prof. Giacomo Comi, at Policlinico di Milano, including Emanuele Frattini and Alessio Di Fonzo of the “Centro Dino Ferrari”, the reference center for diagnosis and therapy of neuromuscular and neurodegenerative diseases at the Hospital and University of Milan.

Starting from a skin biopsy of patients with GBA1 mutations, researchers reprogrammed the fibroblasts in the dermis to obtain induced pluripotent stem cells (iPSC), capable of differentiating into various cell types. Through specific stimulation, these cells were transformed into 3D mini-midbrains, with characteristics very similar to those observed in patient brains.

This innovative model allowed researchers to identify a crucial alteration: the mutated GCase enzyme is retained in the endoplasmic reticulum, a cellular compartment that controls the quality and functionality of many proteins. Its reduced activity favors the accumulation of glucosylceramide and the formation of α-synuclein aggregates similar to Lewy bodies, reproducing the pathological features observed in patient brains and providing new insights into disease mechanisms.

Beyond improving the understanding of the pathology, this specific midbrain organoid allowed the testing of two drugs currently in clinical trials: ambroxol and GZ667161. Both molecules proved effective in significantly reducing the aggregates typical of Parkinson’s disease, opening new perspectives for the development of targeted therapies.

“This is a great international team effort, involving important experts on Parkinson’s disease. The results of this study highlight the potential of midbrain organoids as an innovative tool to deepen our understanding of Parkinson’s disease mechanisms and to promote the development of new targeted therapeutic approaches. Thanks to these advances, research is making significant steps toward the development of increasingly effective treatments, with the goal of improving the quality of life of patients affected by this neurodegenerative condition,” comments Alessio Di Fonzo.

“As with all our research activities, this important work was supported by the Associazione “Centro Dino Ferrari” ETS .”