Researchers have found a way to better control the preclinical generation of key neurons that are damaged in Parkinson’s disease, revealing a new approach to a disease for which there is no cure and few effective treatments.

Efficient Method: Stimulating Stem Cell Differentiation to Produce Neurons in the Midbrain

Parkinson’s disease is the second most common neurological disease after Alzheimer’s disease. On average, around 1 to 2 in 1000 people in the population have Parkinson’s disease. The disease mainly occurs after the age of 50 and particularly affects older men. It leads to a progressive impairment of mobility, pain, sleep and psychological problems.

Scientists at the University of Toronto used an antibody to selectively activate a receptor in a molecular signaling pathway for the development of dopaminergic neurons. These neurons produce dopamine, a neurotransmitter important for brain health. Researchers around the world are working to induce stem cells to differentiate into dopaminergic neurons to replace those that are lost in Parkinson’s patients. However, efforts have been hampered in part by the inability to target specific receptors and areas of the brain.

The researchers in the current study used synthetic antibodies that they had previously developed to target the Wnt signaling pathway. They can selectively activate this signaling pathway to induce midbrain stem cells to develop into neurons by targeting specific receptors in this pathway. The study was recently published in the journal Development.

Most previous research efforts to activate the Wnt signaling pathway have relied on a GSK3 enzyme inhibitor. This method involves multiple signaling pathways for stem cell proliferation and differentiation, which can lead to unintended effects on the newly produced neurons and activation of cells that are not part of the target. The researchers have developed an efficient method to stimulate stem cell differentiation to produce neurons in the midbrain. Another promising result of the study was that the implantation of the artificially produced neurons in a rodent model with Parkinson’s disease led to an improvement in the rodent’s movement restriction.

The researchers’ next step will be to continue with rodents or other suitable models to compare the results of activating the FZD5 receptor and inhibiting GSK3. These experiments will confirm which method is more effective in improving the symptoms of Parkinson’s disease in advance of clinical trials.

Newly Discovered Genetic Mutation Protects Against Parkinson’s Disease

According to a recent study from the USC Leonard Davis School of Gerontology, a previously unidentified genetic mutation in a small protein provides significant protection against Parkinson’s disease and opens a new direction for research into potential treatments.

The variant, located in a mitochondrial microprotein called SHLP2, was found to be highly protective against Parkinson’s disease; individuals with this mutation are only half as likely to develop the disease as those who do not carry the mutation. The aberrant form of the protein is relatively rare and occurs mainly in people of European descent.the results appear in the journal Molecular Psychiatry.

SHLP2 was first discovered in 2016 by Pinchas Cohen at the USC Leonard Davis School and is produced in the mitochondria of the cell. Previous research from the Cohen lab found that SHLP2 is associated with protection against age-related diseases, including cancer, and that levels of the microprotein change in patients with Parkinson’s disease; they increase as the body attempts to counteract Parkinson’s disease pathology, but often fail to build up additional production as the disease progresses.

This latest finding builds on the USC team’s earlier mitochondrial research, and represents an advance at the intersection of longevity science, precision health and microprotein research. This study advances the understanding of why people can get Parkinson’s and how new therapies can be developed for this devastating disease. Since most research is conducted on well-established protein-coding genes in the nucleus, this underscores the importance of studying mitochondrial microproteins as a new approach for the prevention and treatment of diseases of aging.

Parkinson’s Risk Reduced by a Factor of Two

For this study, first author Su-Jeong Kim, an associate assistant professor of gerontology at the USC Leonard Davis School, led a series of experiments using the lab’s proprietary microprotein discovery pipeline, which begins with data-driven analysis to identify variants involved in disease. Thousands of human study participants from the Health & Retirement Study, the Cardiovascular Health Study and the Framingham Heart Study were screened for the SHLP2 variant. By comparing genetic variants in the mitochondrial DNA of Parkinson’s patients and controls, the researchers found a highly protective variant that is present in 1% of Europeans and reduces the risk of Parkinson’s by twofold to 50% of the average.

They then demonstrated that this naturally occurring variant leads to a change in the amino acid sequence and protein structure of SHLP2. The mutation – a single nucleotide polymorphism (SNP) or a single letter change in the protein’s genetic code – is essentially a gain-of-function variant that is associated with higher expression of SHLP2 and makes the microprotein more stable. According to the results, the SHLP2 variant is very stable compared to the more common type and offers better protection against mitochondrial dysfunction.

Using targeted mass spectrometry techniques, the research team was able to detect the presence of the tiny peptide in neurons and found that SHLP2 specifically binds to an enzyme in the mitochondria, known as mitochondrial complex 1. This enzyme is vital and a decrease in its function is associated not only with Parkinson’s disease, but also with strokes and heart attacks. The increased stability of the SHLP2 variant means that the microprotein binds more stably to mitochondrial complex 1, preventing the enzyme’s activity from declining and thus reducing mitochondrial dysfunction. The benefits of the mutant form of SHLP2 were observed in both in vitro experiments on human tissue samples and in mouse models of Parkinson’s disease, the study said.

The data reveal the biological effects of a particular gene variant and the possible molecular mechanisms by which this mutation may reduce the risk of Parkinson’s disease. These findings could guide the development of therapies and provide a roadmap for understanding other mutations in mitochondrial microproteins.