Details

Autor(en) / Beteiligte

• Bakthavachalu, Baskar
• Huelsmeier, Joern
• Sudhakaran, Indulekha P.
• Hillebrand, Jens
• Singh, Amanjot
• Petrauskas, Arnas
• Thiagarajan, Devasena
• Sankaranarayanan, M.
• Mizoue, Laura
• Anderson, Eric N.
• Pandey, Udai Bhan
• Ross, Eric
• VijayRaghavan, K.
• Parker, Roy
• Ramaswami, Mani

Titel

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

Ist Teil von

• Neuron (Cambridge, Mass.), 2018-05, Vol.98 (4), p.754-766.e4

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. •Atx2 is an essential protein, but its IDRs are dispensable for development and viability•Atx2 IDRs are required for efficient RNP-granule assembly•Atx2 IDRs are required for translation-dependent LTM, but not STM•Atx2 IDR deletion prevents C9ORF72 dipeptide repeat or FUS-induced neurodegeneration Ataxin-2 protein is required for LTM formation and implicated in both ALS and SCA-2. Bakthavachalu et al. show that disordered domains of Ataxin-2 promote mRNP granule assembly as well as long-term memory and cytotoxicity in Drosophila ALS models.