The SorCS2-derived macrocycle TT-P34 drives neuroprotection in animal models of neurodegeneration

Mitochondria are critical for sustaining the high energy demands of neuronal activity and their dysregulation is a hallmark of neurodegeneration. Targeting pathways of neurotrophic signaling is a well-established therapeutic strategy to enhance mitochondrial function and mitigate neurodegeneration. The VPS10p domain receptor, SorCS2, has recently emerged as a receptor with neurotrophic signaling capabilities. Here, we design and develop novel SorCS2-derived macrocyclic peptides mimicking receptor activation in vivo. We show that SorCS2-peptides enhance both neurotrophic support and boost metabolism by activating both CREB and AMPK potentially via a CAMKK2-dependent mechanism. This leads to upregulation of the mitochondrial and lysosomal master regulators, PGC1α and TFEB. Treating the zQ175 mouse model of Huntington’s Disease with a lipidated SorCS2 macrocycle, TT-P34, rescues motor and behavioral deficits and preserves synaptic and mitochondrial signatures in the striatum. In addition, treatment of the mitochondria-deficient MPTP-induced mouse model of Parkinson’s Disease leads to amelioration of motor deficits and preserves dopaminergic neurons. Finally, we demonstrate that TT-P34 crosses the blood-brain barrier in non-human primates and estimate a human therapeutic dosing regimen by pharmacodynamic modelling. Together, our findings support the use of TT-P34 as a novel disease-modifying therapy targeting SorCS2-receptor pathway to prevent neurodegeneration.