Deficiency of Perry syndrome-associated p150Glued in midbrain dopaminergic neurons leads to progressive neurodegeneration and endoplasmic reticulum abnormalities

Multiple missense mutations in p150^Glued are linked to Perry syndrome (PS), a rare neurodegenerative disease pathologically characterized by loss of nigral dopaminergic (DAergic) neurons. Here we generated p150^Glued conditional knockout (cKO) mice by deleting p150^Glued in midbrain DAergic neurons. The young cKO mice displayed impaired motor coordination, dystrophic DAergic dendrites, swollen axon terminals, reduced striatal Dopamine Transporter (DAT), and dysregulated dopamine transmission. The aged cKO mice showed loss of DAergic neurons and axons, somatic accumulation of α-synuclein, and astrogliosis. Further mechanistic studies revealed that p150^Glued deficiency in DAergic neurons led to the reorganization of endoplasmic reticulum (ER) in dystrophic dendrites, upregulation of ER tubule-shaping protein reticulon 3, accumulation of DAT in reorganized ERs, dysfunction of COPII-mediated ER export, activation of unfolded protein response, and exacerbation of ER stress-induced cell death. Our findings demonstrate the importance of p150^Glued in controlling the structure and function of ER, which is critical for the survival and function of midbrain DAergic neurons in PS.