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Co-chaperones DNAJA1 and DNAJB6 are critical for regulation of polyglutamine aggregation

Claudio Rodríguez-González1, Shiying Lin1, Sertan Arkan1

  • 1Molecular Neurobiology, Department of Experimental Medical Science, Lund University, BMC B11, 22184, Lund, Sweden.

Scientific Reports
|May 20, 2020
PubMed

Insights

Huntington's disease (HD) involves huntingtin (HTT) gene CAG repeat expansion. DNAJ co-chaperones DNAJA1 and DNAJB6 oppositely regulate HTT protein aggregation, impacting neuronal cell survival.

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Genetics

Background:

  • Huntington's disease (HD) arises from CAG repeat expansion in the huntingtin gene.
  • Expanded polyglutamine (polyQ) in huntingtin protein causes misfolding, aggregation, and neuronal death.
  • DNAJ co-chaperones are vital for transferring proteins to HSP70 chaperones for proper folding.

Purpose of the Study:

  • To investigate the impact of knocking out individual DNAJ genes on polyglutamine aggregation.
  • To determine the role of DNAJA1, DNAJB1, and DNAJB6 in modulating huntingtin protein aggregation.

Main Methods:

  • Utilized HEK293 cells expressing polyglutamine74exon1 huntingtin (polyQ74htt).
  • Employed fluorescence microscopy and filter trap assay (FTA) to quantify polyQ74htt aggregation.
  • Assessed cell death using trypan blue exclusion and propidium iodide (PI) uptake assays.

Main Results:

  • Knockout (KO) of DNAJB6 significantly increased polyQ74htt aggregation (5-fold).
  • KO of DNAJA1 markedly decreased polyQ74htt aggregation (4-fold).
  • DNAJB6 KO cells exhibited increased cell death rates.

Conclusions:

  • DNAJA1 and DNAJB6 differentially regulate polyQ aggregation, with opposing effects.
  • Fine-tuning cellular DNAJ protein levels is crucial for suppressing polyQ aggregation.
  • Modulating DNAJ proteins may offer a therapeutic strategy for Huntington's disease.

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