LRP10 promotes trafficking of progranulin and prosaposin to lysosomes

Mutations in LRP10, a low-density lipoprotein receptor family member, cause familial Parkinsons disease and dementia with Lewy bodies. However, its direct cellular functions remain largely undefined. Using a multidisciplinary approach, our new data shows that LRP10 is required for the efficient trafficking of progranulin and prosaposin to lysosomes. Loss of LRP10 resulted in aberrant Golgi accumulations of progranulin and prosaposin and their reduced abundance in lysosomes. Disease-linked LRP10 missense mutations failed to support this lysosomal trafficking. Moreover, LRP10 KO mice developed striking microgliosis marked by enlarged and hyper-ramified microglia, accompanied by progranulin accumulation in the Golgi. Our results define LRP10 as a positive regulator of progranulin and prosaposin lysosomal protein trafficking and microglia homeostasis and thus shed new light on how its dysfunction may drive neurodegeneration in Parkinsons Disease and dementia with Lewy bodies.