Similar to the majority of neurodegenerative diseases, the pathological hallmark of Motor Neurone Disease (MND) is the presence of protein aggregates in affected motor neurons (MNs). Protein aggregates progress continually from the site of onset to disturb cellular processes, ultimately resulting in neuron degeneration [1]. The only intracellular degradative pathway that can purge the cells of these protein aggregates and dysfunctional organelles is autophagy. Since impaired/reduced autophagy may contribute to MND pathogenesis, upregulating autophagy offers a potential therapeutic option.
This study aimed to develop brain-penetrating peptides with autophagy-inducing activity. We designed a series of peptide analogues of Beclin-1 protein, the master regulator of autophagy. Peptides were modified through cyclisation and conjugated to our previously developed cell-/BBB-penetrating peptide to enhance their cellular uptake and activity. We showed that the peptides can induce autophagy at 5 micromolar concentration in MNs, which is 10-fold more potent than the previously reported autophagy-inducing drugs. More importantly, the most potent peptide analogue significantly decreased the levels of protein (SOD1 and C9ORF72) aggregates associated with MND. Subsequently, the Beclin peptide reduced the toxicity associated with the expression of these aggregate-prone proteins by reducing cleaved caspase-3 activation. Moreover, the peptide was injected in autophagy reporter mice at 10 mg/kg via IV tail vein injection. The level of autophagy was significantly upregulated in spinal cord MNs in the peptide-treated mice compared to the saline group. In conclusion, this study provides evidence for a novel peptide-based approach to enhance autophagy as a unique and safe treatment modality with potential therapeutic benefits in MND and other neurodegenerative diseases.