There is an urgent need for biomaterials that support tissue healing, particularly neuronal regeneration. In a medium throughput screen novel self-assembling peptide (SAP) sequences that form fibrils and stimulated nerve fiber growth of peripheral nervous system (PNS)-derived neurons are identified. Based on the peptide sequences and fibril morphologies and by applying rational data-mining, important structural parameters stimulating neuronal activity are elucidated. Three SAPs (SAP 1e , SAP 2e , and SAP 5c ) enhance adhesion and growth of PNS neurons. These SAPs form 2D and 3D matrices that serve as bioactive scaffolds stimulating cell adhesion and growth. The newly discovered SAPs also support the growth of CNS neurons and glia cells. Subsequently, the potential of SAPs to enhance PNS regeneration in vivo is analyzed. For this, the facial nerve driving whisker movement in mice is injured. Notably, SAPs persist for up to 3 weeks in the injury site indicating highly adhesive properties and stability. After SAP administration, more motor neurons incorporating markers for successive regeneration are observed. Recovery of whisker movement is elevated in SAP-injected mice. In summary, short peptides that form fibrils are identified and the adhesion, growth, and regeneration of neurons have been efficiently enhanced without the necessity to attach hormones or growth factors.

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Expansion of the glutamine tract (poly-Q) in the protein Huntingtin (HTT) causes the neurodegenerative disorder Huntington disease (HD). Emerging evidence suggests that mutant HTT (mHTT) disrupts brain development. To gain mechanistic insights into the neurodevelopmental impact of human mHTT, we engineered induced pluripotent stem cells to introduce a biallelic or monoallelic mutant 70Q expansion or to remove the poly-Q tract of HTT. 70Q introduction caused aberrant development of cerebral organoids with loss of neural progenitor organization. The early neurodevelopmental signature of mHTT highlighted the dysregulation of the protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), a transcription factor involved in mitochondrial integrated stress response. CHCHD2 repression was associated with abnormal mitochondrial morpho-dynamics and elevated resting energy expenditure. Elimination of the poly-Q tract of HTT normalized CHCHD2 expression and mitochondrial defects. Hence, mHTT-mediated disruption of human neurodevelopment is paralleled by aberrant neurometabolic programming mediated by dysregulation of CHCHD2, which could then serve as an early intervention target for HD.