Scientists Develop New Compound That Could Potentially Slow Parkinson’s Progression


Researchers have developed a new compound, called S-181, that can improve nerve cell function and decrease the build-up of disease-related harmful molecules by boosting the activity levels of the enzyme beta-glucocerebrosidase.

That enzyme’s function is known to be compromised in Parkinson’s disease.

The findings, “A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson’s disease,” were published in the journal Science Translational Medicine.

Mutations in the GBA1 gene are one of the most common genetic risk factors for Parkinson’s. The GBA1 gene contains instructions to produce an enzyme, called beta-glucocerebrosidase (GCase), which is active in lysosomes — special compartments within cells that break down and recycle different types of molecules.

If GCase fails to work as it is supposed to, toxic substances accumulate inside dopamine-producing cells, leading to the excessive inflammatory and neurodegenerative processes that are observed in Parkinson’s.

Therefore, and in theory, boosting GCase activity could potentially slow down disease progression.

Northwestern University scientists now took a different approach than the one currently attempted by researchers: instead of trying to fix the mutated version of the GCase enzyme, they attempted to increase the levels of its normal form in cellular and animal models of Parkinson’s.

The team developed a small-molecule modulator of GCase called S-181 and tested its function in dopaminergic neurons. These neurons were derived from induced pluripotent stem cells (iPSC) from sporadic or non-inherited (also known as non-familial) Parkinson’s patients, as well as from individuals with low GCase levels and with mutations in the GBA1, LRRK2, PARK7, or PARKIN genes — all of which have been associated with the neurodegenerative disorder.

iPSCs are master cells that can potentially produce any cell or tissue the body needs to repair itself. They are derived from either skin or blood cells, and then are reprogrammed back into a stem cell-like state, which allows for the development of an unlimited source of almost any type of human cell.

In this case, cells were derived from skin cells, also known as fibroblasts. Because they are derived from patients, the “novel daughter cells” will carry the same genetic defects as those found in the original cells.

S-181 binds to GCase and modulates its activity. Treating these patient-derived neurons with S-181 partially restored lysosomal function and lowered accumulations of Parkinson’s-related toxic molecules, including oxidized dopamine and glucosylceramide. It also decreased accumulations of alpha-synuclein, one of the main components of Parkinson’s hallmark protein deposits — called Lewy bodies.

Mice with a mutated GBA1 gene also were treated with S-181. The treatment boosted the activity of non-mutated GCase and reduced the production of barely active GCase-dependent harmful molecules, decreasing alpha-synuclein build-up in the brain.

“This study highlights wild-type GCase activation as a potential therapeutic target for multiple forms of Parkinson’s disease,” Dimitri Krainc, MD, PhD, chair of neurology and director of the Center for Neurogenetics at Northwestern University Feinberg School of Medicine, said in a press release.

“Our work points to the potential for modulating wild-type GCase activity and protein levels in both genetic and idiopathic forms of PD [Parkinson’s disease] and highlights the importance of personalized or precision neurology in development of novel therapies,” said Krainc, the study’s lead author.

Two years ago, a previous study by the same team showed that some of the molecular features of Parkinson’s are only present in human nerve cells and not in Parkinson’s animal models. Those findings illustrated the importance of investigating the disease mechanism and developing new medications using patient-derived neurons.

“It will be important to examine human neurons to test any candidate therapeutic interventions that target midbrain dopaminergic neurons in PD,” Krainc concluded.

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Wireless Pacemaker-like Device May Offer Real-time Treatment for Parkinson’s, Study Reports

neuromodulator for Parkinson's

A new neuromodulator — a wireless pacemaker-like device — may provide real-time treatment to patients with diseases such as Parkinson’s by monitoring abnormalities and delivering corrective electrical signals to the brain.

The device was described in the study, “A wireless and artefact-free 128-channel neuromodulation device for closed-loop stimulation and recording in non-human primates,” published in the journal Nature Biomedical Engineering.

Recent studies have shown that closed-loop neuromodulation systems could improve deep brain stimulation for treating Parkinson’s disease and other motor disorders. These systems deliver and adjust therapeutic electrical stimulation in response to a patient’s neural state in real time.

Up to this point, it has been difficult, both medically and economically, to apply closed-loop neuromodulation systems in patients with movement disorders, and it hasn’t been clear how to implement strategies for these treatments. Previous attempts were short term, using systems that were not fully implantable.

“In order to deliver closed-loop stimulation-based therapies, which is a big goal for people treating Parkinson’s and epilepsy and a variety of neurological disorders, it is very important to both perform neural recordings and stimulation simultaneously, which currently no single commercial device does,” study author Samantha Santacruz, PhD, now an assistant professor at the University of Texas, said in a press release.

To enable advanced research in closed-loop neuromodulation, “there is a need for a flexible research platform, for testing and implementing these various closed-loop paradigms, that is also wireless, compact, robust and safe,” the researchers wrote in the study.

The researchers, from the University of California, Berkeley and Cortera Neurotechnologies, introduce a new device in this study that allows simultaneous recording and stimulation of the brain. The WAND — wireless artifact-free neuromodulation device — is a miniaturized, autonomous neural interface capable of closed-loop sensing and stimulation while fully canceling stimulation artifacts — recorded electrical signals coming from the device. With this WAND, electrodes are surgically implanted inside the brain, with chips contained in a chassis attached to the outside of the head.

Existing devices can detect neural biomarkers electrical signatures indicative of abnormal brain processes and stimulate the brain in a closed-loop neuromodulation system, but they contain a low number of recording and stimulating channels. WAND improves on these limitations by incorporating a large number of recording and stimulation channels and a wireless data rate to support a large number of streaming channels. The technology also automatically adjusts stimulation parameters.

“The process of finding the right therapy for a patient is extremely costly and can take years. Significant reduction in both cost and duration can potentially lead to greatly improved outcomes and accessibility,” said Rikky Muller, PhD, an assistant professor of electrical engineering at University of California, Berkeley. “We want to enable the device to figure out what is the best way to stimulate for a given patient to give the best outcomes. And you can only do that by listening and recording the neural signatures.”

In a study of non-human primates, WAND enabled long-term recordings of local brain activity and the real-time cancellation of stimulation artifacts. The researchers proved that the closed-loop system device was causing changes in brain activity by using stimulation to create a functional change in the primates’ behavior during a routine task. To this end, the device enables neuroscientific discovery and preclinical investigations of stimulation-based therapeutic interventions.

“While delaying reaction time is something that has been demonstrated before, this is, to our knowledge, the first time that it has been demonstrated in a closed-loop system based on a neurological recording only,” Muller said. “In the future, we aim to incorporate learning into our closed-loop platform to build intelligent devices that can figure out how to best treat you, and remove the doctor from having to constantly intervene in this process.”

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