Results from preclinical studies show the PIG3 protein as a key player in LRRK2-mediated familial Parkinson’s disease.
The findings were discussed in two presentations at the Society for Neuroscience (SfN) 2018 annual meeting in San Diego, California.
Mutations in the LRRK2 gene — the leading genetic cause of Parkinson’s — account for about 1 to 2 percent of all disease cases.
LRRK2 codes for the enzyme leucine-rich repeat kinase 2 (LRKK2), a protein that modifies other proteins’ activities, including signaling, replication, and gene expression.
All LRRK2 disease-causing mutations lead to higher LRKK2 enzyme activity; but the mechanism linking LRRK2 variants and Parkinson’s-related neurodegeneration is unclear.
Researchers used an approach they call “back to biology,” which is based on a platform developed by the biopharmaceutical company Berg, called Interrogative Biology. This platform — fueled by artificial intelligence — allows the analysis of several proteins from the same tissue sample, helping scientists to identify biomarkers that may speed the discovery and development of treatments aimed at promising therapeutic targets and pathways.
In the study “p53 inducible gene 3 (PIG3) directly modulates apoptotic responses in human neuronal models of Parkinson’s disease in vitro,” researchers identified a protein called PIG3 as an important mediator of the damage mutated LRRK2 does to nerve cells.
Researchers compared protein patterns in fibroblasts — specialized cells responsible for ensuring the normal structure of tissues — collected from Parkinson’s patients harboring the LRRK2G2019S mutation, idiopathic (no genetic or other known cause) Parkinson’s patients, and matched healthy volunteers.
Overall, patients with the LRRK2G2019S mutation had higher levels of the PIG3 protein. These were found to correlated with the activation of two enzymes, MKK3 and p38 MAPK, and with a buildup of the p53 protein — a protein that regulates the cell cycle and functions as a tumor suppressor (known as the “guardian of the genome”).
Further experiments with human dopamine-producing nerve cells showed linked higher PIG3 levels to cell death.
While experimental conditions that forced PIG3 production induced cell death, genetic or chemical blocking of PIG3 or LRRK2 activity were able to prevent neurodegeneration.
Researchers also found that PIG3 interacts with an enzyme called catalase, modulating the levels of oxidative stress — which damages cells as a consequence of high levels of oxidant molecules — and, consequently, of cell death.
“Our Back to Biology approach has further identified novel profiles driving disease activity – such as LRRK2 mutation and PIG3 expression – that we believe hold great potential for novel treatments for patients suffering from progressive, debilitating neurodegenerative disorders,” Niven R. Narain, PhD, a Berg co-founder and its CEO, said in a press release.
Researchers reprogrammed fibroblasts from both healthy individuals and LRRK2G2019S Parkinson’s patients to generate inducible-pluripotent stem cells (iPSC). These cells were programmed back into a stem cell-like state, allowing for the development of an unlimited source of any type of human cell.
iPSCs cells, from both patients and healthy controls, were then transformed (differentiated) into neurons, and the team was able to replicate their findings in these nerve cells, additional evidence for the role of PIG3 in Parkinson’s progression.
Next, researchers used the CRISPR/Cas9 system — a gene editing approach — to genetically delete the PIG3 coding gene in these iPSCs. Patients-derived iPSCs lacking the gene showed better cell survival in response to certain death-inducing stimuli.
“Our preliminary findings support the notion that PIG3 might serve as valuable and novel therapeutic target in Parkinson’s-specific pathologies,” researchers wrote.
In the study, “Altered cellular and metabolomic phenotypes observed in LRRK2G2019S patient-specific iPSC-derived neurons are partially rescued in PIG3-deficient cells,” researchers evaluated the deteriorating function of LRRK2G2019S in patient iPSC-derived neurons.
By analyzing electrophysiological — the electric activity associated with nerve cell functions — and metabolomic — chemical processes involved in several cellular processes — profiles in dopaminergic neurons derived from iPSCs, researchers found that Parkinson’s-derived neurons (nerve cells) had different patterns of activity patterns and altered metabolomic profiles.
These included different neuronal firing rates (electrical pulses necessary for nerve cell communication), burst frequencies (oscillations in neuronal activation patterns), and network synchrony (involved in regulating information transmission through the nervous system).
“Taken together, our findings reveal that PIG3 contributes to apoptosis in neuronal models of Parkinson’s disease, and may advance our understanding of the mechanisms behind LRRK2 G2019S-mediated hypersensitivity to environmental neurotoxins, and neuronal dysfunction,” the researchers concluded.
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