Targeting Shp2 as a therapeutic strategy for neurodegenerative diseases

Abstract

The incidence of neurodegenerative diseases (NDs) has increased recently. However, most of the current governance strategies are palliative and lack effective therapeutic drugs. Therefore, elucidating the pathological mechanism of NDs is the key to the development of targeted drugs. As a member of the tyrosine phosphatase family, the role of Shp2 has been studied in tumors, but the research in the nervous system is still in a sporadic state. It can be phosphorylated by tyrosine kinases and then positively regulate tyrosine kinase-dependent signaling pathways. It could also be used as an adaptor protein to mediate downstream signaling pathways. Most of the existing studies have shown that Shp2 may be a potential molecular "checkpoint" against NDs, but its role in promoting degenerative lesions is difficult to ignore as well, and its two-way effect of both activation and inhibition is very distinctive. Shp2 is closely related to NDs-related pathogenic factors such as oxidative stress, mitochondrial dysfunction, excitatory toxicity, immune inflammation, apoptosis, and autophagy. Its bidirectional effects interfere with these pathogenic factors, making it a core component of the feedback and crosstalk network between multiple signaling pathways. Therefore, this article reviews the molecular mechanism of Shp2 regulation in NDs and its regulatory role in various pathogenic factors, providing evidence for the treatment of NDs by targeting Shp2 and the development of molecular targeted drugs.

Fig. 1. Expression and distribution of Shp2 in the brain or cells (from the human protein atlas database).

A Shp2 is highly expressed in multiple brain regions, such as the cerebral cortex, hippocampal formation, amygdala, basal ganglia, and thalamus. the red areas represent the regions of Shp2 expression in the brain. B Shp2 is mainly expressed in the nucleolar margin, actin filaments, nucleoplasm and cytoplasm of cells.

Fig. 2. The structure and activation state of Shp2.

Shp2 has two binding domains (N-SH2 and C-SH2) and a catalytic domain (PTP). In the natural state, N-SH2 binds to PTP to form a self-inhibited nonactivated state. The binding of phosphopeptides to N-SH2 promotes separation from the PTP domain and causes the activation of the Shp2 phosphatase.

Fig. 3. Related therapeutic strategies for NDs and Shp2.

A Eight Frontier therapeutic strategies for NDs. B Strategies targeting Shp2 to treat NDs.

Fig. 4. Signaling pathways regulated by Shp2 in NDs.

Shp2 is involved in a variety of pathophysiological characteristics related to NDs. It can directly or indirectly participate in neuroinflammation through the Ras/Erk, JAK/STAT3, TRIF/TBK1, and MAPK pathways; participate in oxidative stress and mitochondrial dysfunction through STAT3, ANT1, and NLRP3; affect the level of apoptosis-related proteins through Ras/Erk and FAK/PI3K/AKT; and activate autophagy through Pink1/Parkin and AMPK/mTOR. Shp2 has a leading or subordinate function in these signaling pathways and plays a positive or negative two-way regulatory role.