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This commentary provides an overview of the putamen as an established target site for gene therapy in treating aromatic l-amino acid decarboxylase (AADC) deficiency and Parkinson's disease, two debilitating neurological disorders that involve motor dysfunction caused by dopamine deficiencies. The neuroanatomy and the function of the putamen in motor control provide good rationales for targeting this brain structure. Additionally, the efficacy and safety of intraputaminal gene therapy demonstrate that restoration of dopamine synthesis in the putamen by using low doses of adeno-associated viral vector serotype 2 to deliver the hAADC gene is well tolerated. This restoration leads to sustained improvements in motor and nonmotor symptoms of AADC deficiency and improved uptake and conversion of exogenous l-DOPA into dopamine in Parkinson's patients., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)

Introduction : Parkinson's disease is a progressive neurological disorder characterized by the preferential loss of dopaminergic neurons in the substantia nigra, which project to the striatum. The disease is characterized by prominent motor symptoms, which are its cardinal features. Consequently, Parkinson's disease has been primarily considered a disorder of movement. However, increasing evidence has indicated that Parkinson's disease affects not only the motor domain but also the cognitive domain. Increasing evidence indicates that patients with Parkinson's disease have an impaired ability to recognize emotional facial expressions. Recent studies have reported that other socially relevant information from faces, including face-to-trait inferences for traits such as dominance, competence, and trustworthiness, may be processed in subcortical regions, including the amygdala and caudate nucleus. However, the mechanism underlying the processing of face-to-trait inferences for these traits in patients with Parkinson's disease is still unknown. This study aimed to assess the face-to-trait inference ability in patients with Parkinson's disease. Method : Face-to-trait inference ability was assessed using a forced-choice method in patients with Parkinson's disease and age- and sex-matched healthy controls. Results : Overall correct face-to-trait inferences occurred significantly less frequently in the Parkinson's disease group than in the control group. Further analysis revealed a significant interaction between groups and the extent to which facial features were exaggerated. Conclusions : The present results suggest that the sensitivity of face-to-trait processing was linear in the Parkinson's disease group but not in the healthy controls. These deficits may have resulted from dysfunction in subcortical regions, which may also lead to impairment in other social inferential abilities in patients with Parkinson's disease.

Information on how the subcortical brain encodes information required to execute actions or to evaluate others' actions remains scanty. To clarify this link, Fitts'-law tasks for perception and execution were tested in patients with Parkinson's disease (PD). For the perception task, participants were shown apparent motion displays of a person moving their arm between two identical targets and reported whether they judged that the person could realistically move at the perceived speed without missing the targets. For the motor task, participants were required to touch the two targets as quickly and accurately as possible, similarly to the person observed in the perception task. In both tasks, the PD group exhibited, or imputed to others, significantly slower performances than those of the control group. However, in both groups, the relationships of perception and execution with task difficulty were exactly those predicted by Fitts' law. This suggests that despite dysfunction of the subcortical region, motor simulation abilities reflected mechanisms of compensation in the PD group. Moreover, we found that patients with PD had difficulty in switching their strategy for estimating others' actions when asked to do so., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Clinical studies of gene therapy for Parkinson's disease are based on three kinds of strategies. 1. Restoration of dopamine production in the putamen by introducing genes of dopamine-synthesizing enzymes. 2. Protection of nigrostriatal projections by gene transfer of neurotrophic factors into the putamen and substantia nigra. 3. Modulation of subthalamic nucleus neural activity by gene delivery of an enzyme to synthesize inhibitory transmitter y-aminobutyric acid. In all studies, procedures were well tolerated and no adverse effects attributed to viral vectors were reported. The beneficial effects of putaminal gene transfer on motor symptoms have also been confirmed in children with aromatic L-amino acid decarboxylase deficiency. For a neuroprotective strategy, early intervention is necessary before degeneration has proceeded too far.

We overview the 16-kDa proteolipid mediatophore, the transmembrane c-subunit of the V0 sector of the vacuolar proton ATPase (ATP6V0C) that was shown to mediate the secretion of acetylcholine. Acetylcholine, serotonin, and dopamine (DA) are released from cell soma and/or dendrites if ATP6V0C is expressed in cultured cells. Adeno-associated viral vector-mediated gene transfer of ATP6V0C into the caudate putamen enhanced the depolarization-induced overflow of endogenous DA in Parkinson-model mice. Motor impairment was ameliorated in hemiparkinsonian model mice when ATP6V0C was expressed with DA-synthesizing enzymes. The review discusses application in the future as a potential tool for gene therapy, cell transplantation therapy, and inducible pluripotent stem cell therapy in neurological diseases, from the view point of recent findings regarding vacuolar ATPase.

Parkinson's disease (PD), a neurological disease suited to gene therapy, is biochemically characterized by a severe decrease in the dopamine content of the striatum. One current strategy for gene therapy of PD involves local production of dopamine in the striatum achieved by inducing the expression of enzymes involved in the biosynthetic pathway for dopamine. We previously showed that the coexpression of tyrosine hydroxylase (TH) and aromatic-L-amino-acid decarboxylase (AADC), using two separate adeno-associated virus (AAV) vectors, resulted in more effective dopamine production and more remarkable behavioral recovery in 6-hydroxydopamine-lesioned parkinsonian rats, compared with the expression of TH alone. Not only levels of TH and AADC but also levels of tetrahydrobiopterin (BH4), a cofactor of TH, and GTP cyclohydrolase I (GCH), a rate-limiting enzymes for BH4 biosynthesis, are reduced in parkinsonian striatum. In the present study, we investigated whether transduction with separate AAV vectors expressing TH, AADC, and GCH was effective for gene therapy of PD. In vitro experiments showed that triple transduction with AAV-TH, AAV-AADC, and AAV-GCH resulted in greater dopamine production than double transduction with AAV-TH and AAV-AADC in 293 cells. Furthermore, triple transduction enhanced BH4 and dopamine production in denervated striatum of parkinsonian rats and improved the rotational behavior of the rats more efficiently than did double transduction. Behavioral recovery persisted for at least 12 months after stereotaxic intrastriatal injection. These results suggest that GCH, in addition to TH and AADC, is important for effective gene therapy of PD.