RNP-Granule Assembly via Ataxin-2 Disordered Domains Is Required for Long-Term Memory and Neurodegeneration

Neuron. 2018 May 16;98(4):754-766.e4. doi: 10.1016/j.neuron.2018.04.032.


Human Ataxin-2 is implicated in the cause and progression of amyotrophic lateral sclerosis (ALS) and type 2 spinocerebellar ataxia (SCA-2). In Drosophila, a conserved atx2 gene is essential for animal survival as well as for normal RNP-granule assembly, translational control, and long-term habituation. Like its human homolog, Drosophila Ataxin-2 (Atx2) contains polyQ repeats and additional intrinsically disordered regions (IDRs). We demonstrate that Atx2 IDRs, which are capable of mediating liquid-liquid phase transitions in vitro, are essential for efficient formation of neuronal mRNP assemblies in vivo. Remarkably, ΔIDR mutants that lack neuronal RNP granules show normal animal development, survival, and fertility. However, they show defects in long-term memory formation/consolidation as well as in C9ORF72 dipeptide repeat or FUS-induced neurodegeneration. Together, our findings demonstrate (1) that higher-order mRNP assemblies contribute to long-term neuronal plasticity and memory, and (2) that a targeted reduction in RNP-granule formation efficiency can alleviate specific forms of neurodegeneration.

Keywords: ALS; Ataxin-2; C9ORF72; Drosophila; FUS; long-term memory; neurodegeneration; stress granule; therapeutic; translational control.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Animals
  • Ataxin-2 / genetics*
  • Ataxin-2 / metabolism
  • C9orf72 Protein
  • Cytoplasmic Granules / metabolism*
  • Drosophila
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Fertility
  • Heterogeneous-Nuclear Ribonucleoprotein Group F-H
  • Intrinsically Disordered Proteins / genetics*
  • Intrinsically Disordered Proteins / metabolism
  • Memory, Long-Term*
  • Neurodegenerative Diseases / genetics*
  • Ribonucleoproteins / metabolism*
  • Smell
  • Spinocerebellar Ataxias / genetics
  • Survival


  • ATX2 protein, Drosophila
  • Ataxin-2
  • C9orf72 Protein
  • Drosophila Proteins
  • FUS protein, Drosophila
  • Heterogeneous-Nuclear Ribonucleoprotein Group F-H
  • Intrinsically Disordered Proteins
  • Ribonucleoproteins
  • messenger ribonucleoprotein