Publications

Peptide-based supramolecular nanostructures offer a versatile platform with substantial promise for clinical translation in regenerative medicine. These systems allow for the incorporation of biologically active sequences and can be engineered to modulate tissue-specific parameters such as stiffness, diffusivity, and biodegradability. We developed here a bioactive supramolecular nanostructure containing a peptide designed based on glial cell-derived neurotrophic factor. These nanostructures form scaffolds that mimic important trophic effects provided by this growth factor on iPSC-derived human dopaminergic neurons. Our in vitro data show that the nanostructures promote cell viability, confer neuroprotection against 6-hydroxydopamine toxicity, enhance neuronal morphology, facilitate electrophysiological maturation, and induce genes involved in neuronal survival. We also found that the scaffold promoted axonal extension in midbrain human organoids. These findings suggest that the supramolecular system could be useful to improve outcomes in cell-based therapies for Parkinson's disease, where progressive dopaminergic degeneration is a hallmark.

JTD Keywords: Cell-line, Mouse model, Neural transplantation, Neurite outgrowth, Neurotrophic factor, Parkinsons-disease, Rat model, Re, Receptor, Substantia-nigra

Neurotrophic factors are essential not only for guiding the organization of the developing nervous system but also for supporting the survival and growth of neurons after traumatic injury. In the central nervous system (CNS), inhibitory factors and the formation of a glial scar after injury hinder the functional recovery of neurons, requiring exogenous therapies to promote regeneration. Netrin-1, a neurotrophic factor, can initiate axon guidance, outgrowth, and branching, as well as synaptogenesis, through activation of deleted in colorectal cancer (DCC) receptors. We report here the development of a nanofiber-shaped supramolecular mimetic of netrin-1 with monomers that incorporate a cyclic peptide sequence as the bioactive component. The mimetic structure was found to activate the DCC receptor in primary cortical neurons using low molar ratios of the bioactive comonomer. The supramolecular nanofibers enhanced neurite outgrowth and upregulated maturation as well as pre- and postsynaptic markers over time, resulting in differences in electrical activity similar to neurons treated with the recombinant netrin-1 protein. The results suggest the possibility of using the supramolecular structure as a therapeutic to promote regenerative bioactivity in CNS injuries.

JTD Keywords: axon growth, axon guidance, cell-migration, colorectal-cancer, dcc, dopaminergic-neurons, force-field, functional recovery, netrin-1, neurite outgrowth, neuronal maturation, neurotrophic factor, neurotrophicfactor mimetic, synapsis, Axon growth, Axons, Cells, cultured, Central nervous system, Coarse-grained model, Nanofibers, Netrin-1, Neurogenesis, Neuronal maturation, Neurons, Neurotrophic factor mimetic, Peptide amphiphile, Synapsis

Cellular prion protein (PrP(C)) is a glycosyl-phosphatidylinositol-anchored glycoprotein. When mutated or misfolded, the pathogenic form (PrP(SC)) induces transmissible spongiform encephalopathies. In contrast, PrP(C) has a number of physiological functions in several neural processes. Several lines of evidence implicate PrP(C) in synaptic transmission and neuroprotection since its absence results in an increase in neuronal excitability and enhanced excitotoxicity in vitro and in vivo. Furthermore, PrP(C) has been implicated in the inhibition of N-methyl-D-aspartic acid (NMDA)-mediated neurotransmission, and prion protein gene (Prnp) knockout mice show enhanced neuronal death in response to NMDA and kainate (KA). In this study, we demonstrate that neurotoxicity induced by KA in Prnp knockout mice depends on the c-Jun N-terminal kinase 3 (JNK3) pathway since Prnp(%) Jnk3(%) mice were not affected by KA. Pharmacological blockage of JNK3 activity impaired PrP(C)-dependent neurotoxicity. Furthermore, our results indicate that JNK3 activation depends on the interaction of PrP(C) with postsynaptic density 95 protein (PSD-95) and glutamate receptor 6/7 (GluR6/7). Indeed, GluR6-PSD-95 interaction after KA injections was favored by the absence of PrP(C). Finally, neurotoxicity in Prnp knockout mice was reversed by an AMPA/KA inhibitor (6,7-dinitroquinoxaline-2,3-dione) and the GluR6 antagonist NS-102. We conclude that the protection afforded by PrP(C) against KA is due to its ability to modulate GluR6/7-mediated neurotransmission and hence JNK3 activation.

JTD Keywords: Ischemic brain-injury, Prion protein PrP(C), Stress-inducible protein-1, Synaptic plasticity, Neurite outgrowth, Signaling module, Caspase-3 activation, Organotypic cultures, Cerebral-ischemia