Modulation of mutant Huntingtin aggregates and toxicity by human myeloid leukemia factors

Int J Biochem Cell Biol. 2017 Jan:82:1-9. doi: 10.1016/j.biocel.2016.11.008. Epub 2016 Nov 10.

Abstract

Increased poly glutamine (polyQ) stretch at N-terminal of Huntingtin (HTT) causes Huntington's disease. HTT interacts with large number of proteins, although the preference for such interactions with wild type or mutated HTT protein remains largely unknown. HYPK, an intrinsically unstructured protein chaperone and interactor of mutant HTT was found to interact with myeloid leukemia factor 1 (MLF1) and 2 (MLF2). To identify the role of these two proteins in mutant HTT mediated aggregate formation and toxicity in a cell model, both the proteins were found to preferentially interact with the mutated N-terminal HTT. They significantly reduced the number of cells containing mutant HTT aggregates and subsequent apoptosis in Neuro2A cells. Additionally, in FRAP assay, mobile fraction of mutant HTT aggregates was increased in the presence of MLF1 or MLF2. Further, MLF1 could release transcription factors like p53, CBP and CREB from mutant HTT aggregates. Moreover, in HeLa cell co-expressing mutant HTT exon1 and full length MLF1, p53 was released from the aggregates, leading to the recovery of the expression of the GADD45A transcript, a p53 regulated gene. Taking together, these results showed that MLF1 and MLF2 modulated the formation of aggregates and induction of apoptosis as well as the expressions of genes indirectly.

Keywords: Aggregation; Apoptosis; FRAP; Huntington’s disease; MLF1; MLF2.

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • DNA-Binding Proteins
  • Exons
  • Fluorescence Recovery After Photobleaching
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Huntingtin Protein / antagonists & inhibitors*
  • Huntingtin Protein / chemistry
  • Huntingtin Protein / genetics
  • Huntingtin Protein / metabolism
  • Huntington Disease / genetics
  • Huntington Disease / metabolism
  • Huntington Disease / pathology
  • Mice
  • Mutation*
  • Neurons / metabolism*
  • Neurons / pathology
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Peptides / chemistry
  • Peptides / metabolism
  • Protein Aggregation, Pathological / genetics
  • Protein Aggregation, Pathological / pathology
  • Protein Aggregation, Pathological / prevention & control*
  • Protein Interaction Domains and Motifs
  • Proteins / chemistry
  • Proteins / genetics
  • Proteins / metabolism*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • HTT protein, human
  • Huntingtin Protein
  • MLF1 protein, human
  • MLF2 protein, human
  • Nuclear Proteins
  • Peptide Fragments
  • Peptides
  • Proteins
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • Green Fluorescent Proteins
  • polyglutamine