2. Academic Validation
  3. Deficiency of Perry syndrome-associated p150Glued in midbrain dopaminergic neurons leads to progressive neurodegeneration and endoplasmic reticulum abnormalities

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

  • NPJ Parkinsons Dis. 2023 Mar 7;9(1):35. doi: 10.1038/s41531-023-00478-0.
Jia Yu 1 2,  Xuan Yang 3,  Jiayin Zheng 3,  Carmelo Sgobio 4 5,  Lixin Sun 4,  Huaibin Cai 6
Affiliations

Affiliations

  • 1 Basic Research Center, Institute for Geriatrics and Rehabilitation, Beijing Geriatric Hospital, Beijing, 100095, China. jyu319@163.com.
  • 2 Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA. jyu319@163.com.
  • 3 Basic Research Center, Institute for Geriatrics and Rehabilitation, Beijing Geriatric Hospital, Beijing, 100095, China.
  • 4 Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
  • 5 Center for Neuropathology and Prion Research, Ludwig-Maximilians University Munich, Munich, 81377, Germany.
  • 6 Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA. caih@mail.nih.gov.
PMID: 36879021 DOI: 10.1038/s41531-023-00478-0
Abstract

Multiple missense mutations in p150Glued are linked to Perry syndrome (PS), a rare neurodegenerative disease pathologically characterized by loss of nigral dopaminergic (DAergic) neurons. Here we generated p150Glued conditional knockout (cKO) mice by deleting p150Glued 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 p150Glued 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 p150Glued in controlling the structure and function of ER, which is critical for the survival and function of midbrain DAergic neurons in PS.

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