September 29, 2023
Keio University School of Medicine
A collaborative research group from 10 institutions, including Assistant Professor Yoshifumi Abe and Professor Kenji Tanaka of the Department of Neuropsychopharmacology, Institute for Advanced Medical Research, Keio University School of Medicine, has discovered a common molecular pathology in L-DOPA-induced dyskinesia (LID) and tardive dyskinesia (TD) using animal models. Furthermore, by clarifying the conditions (a combination of predisposing and environmental factors) that lead to the development of this pathology, they have deepened the understanding of why some cases develop side effects over time while others do not.
LID is an intractable side effect that occurs when patients with Parkinson's disease take the therapeutic drug L-DOPA for a long period, while TD occurs when patients with psychiatric disorders take antipsychotic drugs for a long period. The pathology common to both was the overexpression of the vesicular GABA transporter (VGAT) in striatal neurons. This was found to cause hypertrophy of the nerve terminals of striatal neurons, enhancing neurotransmission to the next cells they connect to, and leading to the development of motor abnormalities (dyskinesia). It was found that VGAT overexpression is caused by a combination of reduced dopamine signaling in striatal neurons (corresponding to a predisposing factor) and repeated fluctuations in brain dopamine levels (corresponding to an environmental factor). It was also revealed that suppressing fluctuations in brain dopamine levels reduces VGAT expression, leading to a therapeutic effect. This finding not only contributes to the development of treatments for intractable dyskinesia but also provides a new disease model where the accumulation of environmental factors over a long period leads to onset.
The results of this research were published in the online edition of Cell Reports Medicine on September 28, 2023 (US Eastern Standard Time).
Please see below for the full press release.