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

ABSTRACT 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 CREB and AMPK in a CAMKK2-dependent manner. This leads to upregulation of the key transcription factors PGC1α and TFEB and consequentially mitochondrial biogenesis. Furthermore, we show that the lipidated SorCS2 macrocycle, TT-P34, rescues motor behavioral deficits and preserves synaptic and mitochondrial signatures in the zQ175 mouse model of Huntington’s Disease. In addition, treating a MPTP-induced mouse model of Parkinson’s Disease leads to amelioration of behavioral deficits and reduction of dopaminergic loss. Finally, we demonstrate that TT-P34 crosses the blood-brain barrier in non-human primates, and estimate human therapeutic dosing by pharmacodynamic modelling. Together, our findings support the use of TT-P34 as a novel disease-modifying therapy targeting SorCS2-receptor signaling to prevent neurodegeneration.