A Massachusetts Institute of Technology (MIT)-led team has identified distinct midbrain circuits that contributed to both motor and psychiatric symptoms of Parkinson's disease (PD) in animal models. Activating the circuits could reverse both types of symptoms.

In their paper, which was published on June 8, 2022, in Nature, the team acknowledged that especially for the psychiatric symptoms, the clinical relevance is murky, as their findings were "based exclusively on male mice and sex differences are well documented in PD" which means that "future research is needed to determine whether these circuit manipulations are equally effective in female mice. This is particularly important for the rescue of depression-like behaviours, which is a severe mood disorder that is approximately twice as prevalent in women than in men."

Nevertheless, the team was able to identify circuits that could be targeted for a broader attack against PD symptoms.

Neurodegenerative diseases are usually known, especially by the public, for one hallmark symptom. Memory loss is emblematic of Alzheimer's disease.

Those motor symptoms can be treated by deep brain stimulation or by pharmacological treatment with the dopamine precursor L-dopa. The most striking brain change in PD is the death of dopamine-producing neurons in the substantia nigra, and it is the death of these neurons that brings on the clinical symptoms of tremor and rigidity.

But to clinicians, the diseases are far more complicated than that. PD also comes with psychiatric symptoms such as depression or even psychosis. And the motor symptoms, too, extend beyond tremor and rigidity. PD patients have deficits in motor learning that cannot be explained by their deficits in movement itself.

In their experiments, which were published on June 8, 2022, in Nature, the investigators looked at thalamic circuits that might contribute to the motor learning and psychiatric symptoms of PD. The thalamus is a midbrain structure that integrates input from a wide range of sensory sources, and sends those signals on to the cortex as well as other midbrain structures.

Previous work had identified the parafascicular nucleus of the thalamus as one of the structures that degenerates in PD patients, prompting the investigators to use circuit tracing methods to look for more specific circuits that might be involved.

"Understanding different symptoms at a circuit level can help guide us in the development of better therapeutics," Guoping Feng, the James W. and Patricia T. Poitras Professor in Brain and Cognitive Sciences at MIT, a member of the Broad Institute of Harvard and MIT, and the associate director of the McGovern Institute for Brain Research at MIT, said in a press release.

The team identified three distinct signaling pathways originating in the parafascicular thalamus that projected to the caudate-putamen, which is part of the basal ganglia; the subthalamic nucleus, which is the area where therapeutic deep brain stimulation is applied in PD; and the nucleus accumbens, which has been linked to some psychiatric symptoms of PD.

They then showed that manipulating those circuits – either through inhibition or activation could improve motor learning and psychiatric symptoms of PD in male mice.

The team is currently using RNA sequencing to identify specific druggable targets in the circuits they have identified.

Additional PD studies

Clinical progress, too, was reported this week for PD. In the June 8, 2022, issue of Science Translational Medicine, investigators from Denali Therapeutics reported both preclinical and phase I safety data on its orally administered LRRK2 inhibitor DNL-201.

In addition, investigators at Brigham and Women's Hospital identified a new role for alpha-synuclein, a protein that forms aggregates in PD. Mutations in alpha-synuclein were the first identified genetic cause in familial PD 25 years ago. The researchers showed that when alpha-synuclein accumulated, it began to interact with a different set of proteins than the nonaggregated version. This in turn impaired its regular interactions with mRNA-processing organelles, which affected mRNA in PD-relevant pathways.

The work "sheds new light on alpha-synuclein biology and the pathophysiology of synucleinopathies and genetic drivers of disease vulnerability," the authors wrote. "Our data open up new ways of considering the role of alpha-synuclein in health and disease, in different cellular compartments, and in different cell types."