NOTCH2NLC Intermediate-Length Repeat Expansions Are Associated with Parkinson Disease

Ann Neurol. 2021 Jan;89(1):182-187. doi: 10.1002/ana.25925. Epub 2020 Oct 19.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biopsy
  • Brain / pathology
  • Cohort Studies
  • Female
  • Humans
  • Intranuclear Inclusion Bodies / metabolism
  • Intranuclear Inclusion Bodies / pathology
  • Male
  • Middle Aged
  • Neurodegenerative Diseases / diagnosis
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology*
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology*
  • Pedigree
  • Receptor, Notch2 / metabolism

Substances

  • NOTCH2 protein, human
  • Receptor, Notch2

Supplementary concepts

  • Neuronal intranuclear inclusion disease