Brain region- and age-dependent dysregulation of p62 and NBR1 in a mouse model of Huntington's disease

Neurobiol Dis. 2013 Apr:52:219-28. doi: 10.1016/j.nbd.2012.12.008. Epub 2013 Jan 4.


Huntington's disease is characterized by the formation of protein aggregates, which can be degraded by macroautophagy. Here, we studied protein levels and intracellular distribution of p62 and NBR1, two macroautophagy cargo receptors, during disease progression. In R6/1 mice, p62 and NBR1 protein levels were decreased in all brain regions analyzed early in the disease, whereas at late stages they accumulated in the striatum and hippocampus, but not in the cortex. The accumulation of p62, but not NBR1, occurred in neuronal nuclei, where it co-localized with mutant huntingtin inclusions, both in R6/1 and Huntington's disease patients. Moreover, exportin-1 was selectively decreased in old R6/1 mice brain, and could worsen p62 nuclear accumulation. In conclusion, p62 interacts with mutant huntingtin and is retained in the nucleus along the progression of the disease, mostly in striatal and hippocampal neurons. Thus, cytoplasmic NBR1 might be important to maintain basal levels of selective macroautophagy in these neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Cell Nucleus / metabolism
  • Cerebral Cortex / metabolism*
  • Corpus Striatum / metabolism*
  • Cytoplasm / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Exportin 1 Protein
  • Hippocampus / metabolism*
  • Humans
  • Huntingtin Protein
  • Huntington Disease / metabolism*
  • Inclusion Bodies / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Karyopherins / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism
  • Nuclear Proteins / metabolism
  • Organ Specificity
  • Proteins / metabolism*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Transcription Factor TFIIH
  • Transcription Factors / metabolism*


  • Gtf2h1 protein, mouse
  • Htt protein, mouse
  • Huntingtin Protein
  • Intracellular Signaling Peptides and Proteins
  • Karyopherins
  • Nbr1 protein, mouse
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • Transcription Factor TFIIH