iPSC modeling of young-onset Parkinson's disease reveals a molecular signature of disease and novel therapeutic candidates.
Nat Med
; 26(2): 289-299, 2020 02.
Article
en En
| MEDLINE
| ID: mdl-31988461
ABSTRACT
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Enfermedad de Parkinson
/
Células Madre Pluripotentes Inducidas
/
Mutación
Límite:
Adult
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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