Protein's Role in Insulin Signaling Could Have Implications for Gene Therapy

Protein tyrosine phosphatase receptor type J (PTPRJ) is a negative regulator of insulin signaling in neuronal cells, according to a new study, and appears to have a role in nervous system development.

The findings, which were reported in the Journal of Neuroendocrinology, could have implications for the use of gene therapy in the prevention and treatment of insulin resistance–associated diseases.¹

The findings could have implications for the use of gene therapy in the prevention and treatment of insulin resistance-associated diseases. | Image Credit: © Dr_Microbe - stock.adobe.com

Corresponding author Kai Kappert, MD, of Charité University Medicine Berlin, and colleagues noted that type 2 diabetes (T2D) is associated with insulin resistance, which occurs in insulin-sensitive organs like the liver, muscle, and adipose tissue. However, they said insulin resistance can also occur in the brain independent of peripheral resistance.

“Numerous studies indicate that central insulin resistance might be a common denominator of T2D, obesity, and cognitive impairments,” they wrote.

A study published earlier this year concluded that insulin resistance could lead to Alzheimer’s disease, and that the reverse could also be true.² It followed research linking insulin resistance to Parkinson disease, major depressive disorder, and other neurodegenerative disorders.

Yet, while a significant amount of research has found associations between insulin resistance and disease, the underlying mechanisms responsible for the associations remain unclear.

In the new study, Kappert and colleagues zeroed in on the protein tyrosine phosphatase (PTP) enzyme family, the members of which are involved in modulating numerous signaling pathways associated with metabolism.¹

“Defined PTPs act as endogenous inhibitors of insulin signaling by dephosphorylating tyrosine residues of the insulin receptor (INSR),” they wrote.

That’s why aberrant PTPs are seen as a potential therapeutic target for T2D, the authors said.

The receptor PTPRJ has become a topic of interest because it has been identified as a negative regulator of insulin signaling in murine models. Previous research by Kappert and colleagues has shown that mice who were deficient in PTPRJ had greater insulin sensitivity and skeletal muscle and liver tissue, “leading to improved glucose tolerance and reduced body weight.”

However, insulin also has a role in the growth of neurites and thus PTPRJ may also affect neuronal cells. To better understand the potential impacts, Kappert and colleagues used gene editing to generate a Ptprj knockout cell model in the murine neuroblast cell line Neuro2a. They found that Ptprj knockout cells had enhanced insulin signaling.

“Additionally, by applying a PLA [proximity ligation] assay, we provide proof of a direct interaction between PTPRJ and the INSR in neurons, which was elevated when cells were subjected to insulin, indicating the recruitment of PTPRJ to INSR upon insulin stimulation,” they explained.

Kappert and colleagues used RNA sequencing gene expression analysis to find gene clusters linked with glucose uptake and metabolism and genes involved in the synthesis of lipids that were upregulated when PTPRJ was deficient.

The authors said 16 calcium ion (Ca2+) transporters were differentially expressed in Ptprj knockout cells, most of which were upregulated, suggesting a role for PTPRJ in neurotransmission through Ca2+ regulation.

When Kappert and colleagues looked at the expression of cellular stress markers, they found that several genes associated with endoplasmic reticulum stress and unfolded protein response were upregulated in Ptprj knockout cells.

“On a functional level, PTPRJ deficiency compromised cell differentiation and neurite outgrowth, suggesting a role in nervous system development,” they concluded.

Kappert and colleagues said their findings show that PTPRJ “plays a pivotal role” in insulin signaling regulation and neuritogenesis. They said it also can be the basis of further follow-up studies to better understand the role of PTPRJ within the brain, which could lead to therapeutic advances, potentially for multiple diseases.

References

1. Ulke J, Chopra S, Kadiri OL, et al. PTPRJ is a negative regulator of insulin signaling in neuronal cells, impacting protein biosynthesis, and neurite outgrowth. J Neuroendocrinol. Published online September 10, 2024. doi:10.1111/jne.13446
2. Abosharaf HA, Elsonbaty Y, Tousson E, M Mohamed T. Alzheimer's disease-related brain insulin resistance and the prospective therapeutic impact of metformin. J Neuroendocrinol. 2024;36(1):e13356. doi:10.1111/jne.13356