RESUMO
NOTCH2NLC GGC repeat expansions were recently identified in neuronal intranuclear inclusion disease (NIID); however, it remains unclear whether they occur in other neurodegenerative disorders. This study aimed to investigate the role of intermediate-length NOTCH2NLC GGC repeat expansions in Parkinson disease (PD). We screened for GGC repeat expansions in a cohort of 1,011 PD patients and identified 11 patients with intermediate-length repeat expansions ranging from 41 to 52 repeats, with no repeat expansions in 1,134 controls. Skin biopsy revealed phospho-alpha-synuclein deposition, confirming the PD diagnosis in 2 patients harboring intermediate-length repeat expansions instead of NIID or essential tremor. Fibroblasts from PD patients harboring intermediate-length repeat expansions revealed NOTCH2NLC upregulation and autophagic dysfunction. Our results suggest that intermediate-length repeat expansions in NOTCH2NLC are potentially associated with PD. ANN NEUROL 2021;89:182-187.
Assuntos
Doenças Neurodegenerativas/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Adulto , Idoso , Biópsia , Encéfalo/patologia , Estudos de Coortes , Feminino , Humanos , Corpos de Inclusão Intranuclear/metabolismo , Corpos de Inclusão Intranuclear/patologia , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/metabolismo , Linhagem , Receptor Notch2/metabolismoRESUMO
Here, we describe the generation of an induced pluripotent stem cell (iPSC) line, from a female patient diagnosed with Parkinson's disease (PD). The patient carries a heterozygous intermediate-length GGC repeat expansions mutation in the NOTCH2NLC gene. Skin fibroblasts were reprogrammed using the non-integrating Sendai virus technology to deliver Klf4, OCT3/4, SOX2 and c-MYC factors. The generated iPSC line (ZZUi020-A) presented with expression of common pluripotency markers, showed potential of differentiating into derivatives of the three germ layers, and displayed a normal karyotype. The clone ZZUi020-A is presented thereafter, it can be used to study the mechanisms underlying NOTCH2NLC-PD pathogenesis.
Assuntos
Células-Tronco Pluripotentes Induzidas , Doença de Parkinson , Diferenciação Celular , Células Cultivadas , Feminino , Camadas Germinativas , Heterozigoto , Humanos , Fator 4 Semelhante a Kruppel , Mutação , Doença de Parkinson/genéticaRESUMO
We screened the RFC1 intronic AAGGG repeat expansions in late-onset ataxia cases, MSA patients and controls. The data suggested that no biallelic repeat expansion carrier was found in our cohort and the heterozygous intronic AAGGG repeat expansions may not lead to an increased risk of late-onset ataxia or MSA.