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iPSC modeling of young-onset Parkinson's disease reveals a molecular signature of disease and novel therapeutic candidates.
Laperle, A H; Sances, S; Yucer, N; Dardov, V J; Garcia, V J; Ho, R; Fulton, A N; Jones, M R; Roxas, K M; Avalos, P; West, D; Banuelos, M G; Shu, Z; Murali, R; Maidment, N T; Van Eyk, J E; Tagliati, M; Svendsen, C N.
Afiliación
  • Laperle AH; Cedars-Sinai Board of Governors Regenerative Medicine Institute, Los Angeles, CA, USA.
  • Sances S; Cedars-Sinai Board of Governors Regenerative Medicine Institute, Los Angeles, CA, USA.
  • Yucer N; Cedars-Sinai Board of Governors Regenerative Medicine Institute, Los Angeles, CA, USA.
  • Dardov VJ; Cedars-Sinai Board of Governors Regenerative Medicine Institute, Los Angeles, CA, USA.
  • Garcia VJ; Cedars-Sinai Board of Governors Regenerative Medicine Institute, Los Angeles, CA, USA.
  • Ho R; Cedars-Sinai Board of Governors Regenerative Medicine Institute, Los Angeles, CA, USA.
  • Fulton AN; Cedars-Sinai Board of Governors Regenerative Medicine Institute, Los Angeles, CA, USA.
  • Jones MR; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Roxas KM; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Avalos P; Cedars-Sinai Board of Governors Regenerative Medicine Institute, Los Angeles, CA, USA.
  • West D; Cedars-Sinai Board of Governors Regenerative Medicine Institute, Los Angeles, CA, USA.
  • Banuelos MG; Cedars-Sinai Board of Governors Regenerative Medicine Institute, Los Angeles, CA, USA.
  • Shu Z; Cedars-Sinai Board of Governors Regenerative Medicine Institute, Los Angeles, CA, USA.
  • Murali R; Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
  • Maidment NT; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Van Eyk JE; Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.
  • Tagliati M; Research Division of Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Svendsen CN; Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
Nat Med ; 26(2): 289-299, 2020 02.
Article en En | MEDLINE | ID: mdl-31988461
Young-onset Parkinson's disease (YOPD), defined by onset at <50 years, accounts for approximately 10% of all Parkinson's disease cases and, while some cases are associated with known genetic mutations, most are not. Here induced pluripotent stem cells were generated from control individuals and from patients with YOPD with no known mutations. Following differentiation into cultures containing dopamine neurons, induced pluripotent stem cells from patients with YOPD showed increased accumulation of soluble α-synuclein protein and phosphorylated protein kinase Cα, as well as reduced abundance of lysosomal membrane proteins such as LAMP1. Testing activators of lysosomal function showed that specific phorbol esters, such as PEP005, reduced α-synuclein and phosphorylated protein kinase Cα levels while increasing LAMP1 abundance. Interestingly, the reduction in α-synuclein occurred through proteasomal degradation. PEP005 delivery to mouse striatum also decreased α-synuclein production in vivo. Induced pluripotent stem cell-derived dopaminergic cultures reveal a signature in patients with YOPD who have no known Parkinson's disease-related mutations, suggesting that there might be other genetic contributions to this disorder. This signature was normalized by specific phorbol esters, making them promising therapeutic candidates.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Parkinson / Células Madre Pluripotentes Inducidas / Mutación Límite: Adult / Animals / Humans Idioma: En Revista: Nat Med Asunto de la revista: BIOLOGIA MOLECULAR / MEDICINA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Parkinson / Células Madre Pluripotentes Inducidas / Mutación Límite: Adult / Animals / Humans Idioma: En Revista: Nat Med Asunto de la revista: BIOLOGIA MOLECULAR / MEDICINA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos