Activation of TMEM175 by small molecules to clear α-synuclein aggregates

Aggregates of α-synuclein in Parkinson’s disease (PD) could be removed by the upregulation of transmembrane protein 175 (TMEM175) but its structure is not fully elucidated to understand the therapeutic potential. 

The researchers in this study determine three cryo-EM structures of human TMEM175 bound to synergistic agonists binding at two discrete sites and reveal its activation mechanisms.

The authors demonstrate that the agonists DCY1020/1040 binds at the interface between two subunits, inducing an open conformation further augmented by the synergistic agonist TUG-891. 

They show that these 3 agonists enhance the lysosomal clearance of pathological α-synuclein and rescue functional deficits of PD-related TMEM175 variants in neurons.

https://www.cell.com/neuron/fulltext/S0896-6273(25)00556-2

https://sciencemission.com/activation-of-TMEM175-by-small-molecule