Signaling modulators in neurons and glial cells

Neurotrophic factors and their receptors have been in the focus for the development of therapeutic treatments for neurological and psychiatric disorders over many years. Unfortunately, growth factor therapies have been largely unsuccessfull in the past. It became clear that receptor tyrosine kinases and their signaling pathways may not be sufficiently activated in the aging brain to exert significant neuroprotective, neurorestorative and stimulatory effects on diseased neurons (possibly due to receptor down-regulation or truncation). Therefore, the aim of our laboratory is to identify intracellular signaling molecules downstream of growth factor receptors which may act as pharmacological targets to increase pro-survival and pro-regenerative mechanisms in the diseased peripheral and central nervous system.

 

Sprouty proteins form a small family of negative feedback inhibitors of growth factor induced intracellular signaling, in particular, the RAS/RAF/MEK/ERK pathway. In the nervous system, down-regulation or knock-out of Sprouties promotes recovery from mechanical, vascular or excitotoxic brain lesions. Applying three different in vivo lesion models we demonstrated that reduction of Sprouties in neurons and glial cells improves neuronal survival and axonal regeneration in the central and peripheral nervous system.

 

We have shown that primary sensory neurons dissociated from Sprouty2 knock-out ganglia exhibit elevated ERK activity and enhanced axon outgrowth. Following sciatic nerve crush, significantly more myelinated axons regenerate in Sprouty2+/- mice which is accompanied by faster recovery of sensomotor performance, higher number of motor endplates in distal muscles and increased expression of GAP-43 (Marvaldi et al. 2015).

 

With regard to the CNS, injections of siRNAs against Sprouties into rat brains reduce the lesion size in response to endothelin-induced vasoconstriction (a model for stroke, Klimaschewski et al. 2015). In another CNS lesion model, kainate-induced epileptogenesis, secondary brain damage is significantly diminished in Sprouty2/4 heterozygous knockouts. These mice exhibit less neuronal loss than their wildtype littermates after kainate injection into the hippocampus which is accompanied by reduced neuronal migration (dispersion of granule cells) and increased astroglial proliferation (Thongrong et al. 2016).

 

Sprouty2 is also a key regulator of glioma formation in the brain (Park et al. 2018). Targeting Sprouty2 sensitizes GBM cells to DNA damage response resulting in decreased tumorigenic capacity. Interestingly, Sprouty2 expression is up-regulated in malignant gliomas and correlates with reduced survival in patients. In contrast to primary astrocytes, knockdown of Sprouty2 significantly impaired proliferation of glial tumors in vitro and in vivo. Silencing of Sprouty2 increased EGF-induced ERK and AKT activation concomitant with premature S-phase entry of GBM cells. Consistent with these findings, DNA damage response and cytotoxicity were increased. Therefore, interference with Sprouties may provide a novel therapeutic strategy to prolong ERK activation under various pathological conditions. For more details have a look at our recent review article.

Funding

Our research is supported by the Austrian Science Fund (FWF), Tyrol Science Fund and by the MUI-START program.