Loss of tau expression attenuates neurodegeneration associated with α-synucleinopathy

Scott Vermilyea, Anne Christensen, Joyce P Meints, Balvindar Singh, Hector Martell Martinez, Md Razaul Karim, Michael K. Lee

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Neuronal dysfunction and degeneration linked to α-synuclein (αS) pathology is thought to be responsible for the progressive nature of Parkinson’s disease and related dementia with Lewy bodies. Studies have indicated bidirectional pathological relationships between αS pathology and tau abnormalities. We recently showed that A53T mutant human αS (HuαS) can cause post-synaptic and cognitive deficits that require microtubule-associated protein tau expression. However, the role of tau in the development of αS pathology and subsequent neuronal dysfunction has been controversial. Herein, we set out to determine the role of tau in the onset and progression of αS pathology (α-synucleinopathy) using a transgenic mouse model of α-synucleinopathy lacking mouse tau expression. Methods: Transgenic mice expressing A53T mutant HuαS (TgA53T) were crossed with mTau−/− mice to generate TgA53T/mTau−/−. To achieve more uniform induction of α-synucleinopathy in mice, we used intramuscular injections of αS preformed fibrils (PFF) in non-transgenic (nTg), TgA53T, TgA53T/mTau−/−, and mTau−/− mice. Motor behavior was analyzed at 70 days post inoculation (dpi) of PFF and tissues for biochemical and neuropathological analysis were collected at 40 dpi, 70 dpi, and end stage. Results: Loss of tau expression significantly delayed the onset of motor deficits in the TgA53T model and the progression of α-synucleinopathy disease, as evidenced by a significant reduction in histopathological and behavioral markers of neurodegeneration and disease, and a significant improvement in survival. In vitro application of PFF to primary mouse hippocampal neurons demonstrated no changes in PFF uptake and processing or pS129 αS aggregation as a function of tau expression. However, PFF-induced neurotoxicity, including morphological deficits in nTg neurons, was prevented with tau removal. Conclusions: Collectively, our data suggest that tau is likely acting downstream of αS pathology to affect neuronal homeostasis and survival. This work further supports the investigation of tau in α-synucleinopathies to identify novel disease-modifying therapeutic strategies.

Original languageEnglish (US)
Article number34
JournalTranslational Neurodegeneration
Volume11
Issue number1
DOIs
StatePublished - Dec 2022

Bibliographical note

Funding Information:
This work was supported by grants from the National Institutes of Health (NIH) to MKL: R01-NS108686, R56-NS112540, R01-NS092093, R01-NS086074, and the Aligning Science Across Parkinson’s (ASAP-000592) grant administered through the Michael J. Fox Foundation for Parkinson’s Research (MJFF).

Publisher Copyright:
© 2022, The Author(s).

Keywords

  • Lewy body disease
  • Neurodegeneration
  • Parkinson’s disease
  • Tau
  • α-Synuclein

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