Telomere shortening leads to an acceleration of synucleinopathy and impaired microglia response in a genetic mouse model

Annika Scheffold, Inge R Holtman, Sandra Dieni, Nieske Brouwer, Sarah-Fee Katz, Billy Michael Chelliah Jebaraj, Philipp J Kahle, Bastian Hengerer, André Lechel, Stephan Stilgenbauer, Erik W G M Boddeke, Bart J L Eggen, Karl-Lenhard Rudolph, Knut Biber*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Parkinson's disease is one of the most common neurodegenerative disorders of the elderly and ageing hence described to be a major risk factor. Telomere shortening as a result of the inability to fully replicate the ends of linear chromosomes is one of the hallmarks of ageing. The role of telomere dysfunction in neurological diseases and the ageing brain is not clarified and there is an ongoing discussion whether telomere shortening is linked to Parkinson's disease. Here we studied a mouse model of Parkinson's disease (Thy-1 [A30P] a-synuclein transgenic mouse model) in the background of telomere shortening (Terc knockout mouse model). a-synuclein transgenic mice with short telomeres (aSYN(tg/tg) G3Terc(-/-)) developed an accelerated disease with significantly decreased survival. This accelerated phenotype of mice with short telomeres was characterized by a declined motor performance and an increased formation of a-synuclein aggregates. Immunohistochemical analysis and mRNA expression studies revealed that the disease end-stage brain stem microglia showed an impaired response in aSYN(tg/tg) G3Terc(-/-) microglia animals. These results provide the first experimental data that telomere shortening accelerates a-synuclein pathology that is linked to limited microglia function in the brainstem.

Original languageEnglish
Article number87
Number of pages17
JournalActa neuropathologica communications
Volume4
Issue number87
DOIs
Publication statusPublished - 22-Aug-2016

Keywords

  • Parkinson's disease
  • alpha-synuclein
  • Telomeres
  • Microglia
  • IDIOPATHIC PARKINSONS-DISEASE
  • AGGREGATED ALPHA-SYNUCLEIN
  • ALZHEIMERS-DISEASE
  • IN-VIVO
  • LEWY BODIES
  • NEURODEGENERATIVE DISEASES
  • NUCLEAR RECEPTORS
  • SUBSTANTIA-NIGRA
  • TRANSGENIC MICE
  • MYELOID CELLS

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