Systemic administration of a novel Beclin 1-derived peptide significantly upregulates autophagy in the spinal motor neurons of autophagy reporter mice.

Autophagy, an intracellular degradation system, plays a vital role in protecting cells by clearing damaged organelles, pathogens, and protein aggregates. Autophagy upregulation through pharmacological interventions has gained significant attention as a potential therapeutic avenue for proteinopathies. Here, we report the development of an autophagy-inducing peptide (BCN4) derived from the Beclin 1 protein, the master regulator of autophagy. To deliver the BCN4 into cells and the central nervous system (CNS), it was conjugated to our previously developed cell and blood-brain barrier-penetrating peptide (CPP). CPP-BCN4 significantly upregulated autophagy and reduced protein aggregates in motor neuron (MN)-like cells. Moreover, its systemic administration in a reporter mouse model of autophagy resulted in a significant increase in autophagy activity in the spinal MNs. Therefore, this novel autophagy-inducing peptide with a demonstrated ability to upregulate autophagy in the CNS has significant potential for the treatment of various neurodegenerative diseases with protein aggregates as a characteristic feature.