Nuclear and neuritic distribution of serine-129 phosphorylated α-synuclein in transgenic mice

H. Schell, T. Hasegawa, M. Neumann, P. J. Kahle

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85 Citations (Scopus)

Abstract

Parkinson's disease and dementia with Lewy bodies are very frequent neurological disorders of the elderly. Mutations in the α-synuclein (αSYN) gene cause Parkinson's disease, often associated with dementia. Neuropathologically these diseases are characterized by the presence of Lewy bodies and Lewy neurites, intraneuronal inclusions mostly composed of αSYN protein fibrils. Moreover, αSYN is phosphorylated at S129 (phospho-serine-129 [PSer129]) in neuropathological lesions. Using our (Thy1)-[A30P]αSYN transgenic mouse model that develops age-dependent impairment in fear conditioning behavior, we investigated PSer129 immunostaining in the brain. We found distinct staining patterns using new, sensitive monoclonal antibodies. Somal and nuclear PSer129 immunoreactivity increased with age in hippocampal and cortical areas as well as the lateral/basolateral amygdalar nuclei and was present also in young, pre-symptomatic mice, but not wild-type controls. The tendency of PSer129 immunostaining to accumulate in the nucleus was confirmed in cell culture. (Thy1)-[A30P]αSYN transgenic mice further developed age-dependent, specific neuritic/terminal αSYN pathology in the medial parts of the central amygdalar nucleus and one of its projection areas, the lateral hypothalamus. Interestingly, this type of PSer129 neuropathology was thioflavine S negative, unlike the Lewy-like neuropathology present in the brain stem of (Thy1)-[A30P]αSYN mice. Thus, αSYN becomes phosphorylated in distinct parts of the brain in this α-synucleinopathy mouse model, showing age-dependent increases of nuclear PSer129 in cortical brain areas and the formation of neuritic/terminal PSer129 neuropathology with variable amyloid quality within the fear conditioning circuitry and the brain stem.

Original languageEnglish
Pages (from-to)796-804
Number of pages9
JournalNeuroscience
Volume160
Issue number4
DOIs
Publication statusPublished - 2009 Jun 2
Externally publishedYes

Keywords

  • Lewy body
  • Parkinson's disease
  • cognition
  • dementia
  • fear conditioning
  • synuclein

ASJC Scopus subject areas

  • Neuroscience(all)

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