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A42 Reactive astrocytes promote proteostasis in huntington’s disease
  1. Laurene Abjean1,
  2. Lucile Ben Haim1,
  3. Maria Angeles Carrillo-de Sauvage1,
  4. Anne-Sophie Hérard1,
  5. Céline Derbois2,
  6. Fanny Petit1,
  7. Pauline Gipstein1,
  8. Martine Guillermier1,
  9. Mylène Gaudin1,
  10. Sueva Bernier1,
  11. Noëlle Dufour1,
  12. Alexis Bémelmans1,
  13. Jean-François Deleuze2,
  14. Philippe Hantraye1,
  15. Gilles Bonvento1,
  16. Robert Olaso2,
  17. Emmanuel Brouillet1,
  18. Carole Escartin1
  1. 1UMR9199, CEA CNRS University Paris Sud and MIRCen, Institut de Biologie François Jacob, CEA, Fontenay-aux-Roses, France
  2. 2CNRGH, Institut de Biologie François Jacob, CEA, Evry, France

Abstract

Astrocytes are essential partners for neurons and their role in Huntington’s disease (HD) is emerging. In HD, astrocytes change and become reactive. Astrocyte reactivity is characterized by morphological changes but its functional impact is still unclear.

To understand the roles of reactive astrocytes in HD, we have developed viral vectors that infect selectively astrocytes in vivo and either block or induce reactivity, through manipulation of the JAK2-STAT3 pathway. We used these vectors to modulate astrocyte reactivity in two complementary mouse models of HD [knock-in Hdh140 mice and lentivirus-mediated expression of a fragment of mutated Huntingtin (mHtt) in striatal neurons].

In these two models, we found that reactive astrocytes decrease the number and size of mHtt aggregates. How can reactive astrocytes reduce the aggregation of mHtt within neurons? We performed whole-genome transcriptomic analysis of acutely sorted reactive astrocytes to identify genes regulated by the JAK2-STAT3 pathway in astrocytes. We found an enrichment in genes linked to autophagy-lysosome and ubiquitin-proteasome systems, suggesting that reactive astrocytes have an enhanced capacity for protein degradation and could siphon mHtt away from neurons. Moreover, we identified several chaperones upregulated in reactive astrocytes. Chaperones prevent protein aggregation and can be released extracellularly. They could reduce mHtt aggregation within neurons themselves.

Our data show that astrocytes develop a protective response in HD that involves bidirectional signaling with neurons to reduce mHtt aggregation. Reactive astrocytes are not only defective cells as usually reported, but also acquire enhanced capacities to promote mHtt clearance, which has strong therapeutic relevance for HD.

  • astrocyte
  • aggregation
  • neuron-glia interaction
  • proteostasis
  • mouse models

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