Fat cadherins in mouse models of degenerative ataxias

Sci Rep. 2019 Nov 6;9(1):16155. doi: 10.1038/s41598-019-52684-7.

Abstract

Autophagy is a lysosomal degradation pathway that plays an essential role in neuronal homeostasis and is perturbed in many neurological diseases. Transcriptional downregulation of fat was previously observed in a Drosophila model of the polyglutamine disease Dentatorubral-pallidoluysian atrophy (DRPLA) and this was shown to be partially responsible for autophagy defects and neurodegeneration. However, it is still unclear whether a downregulation of mammalian Fat orthologues is associated with neurodegeneration in mice. We hereby show that all four Fat orthologues are transcriptionally downregulated in the cerebellum in a mouse model of DRPLA. To elucidate the possible roles of single Fat genes, this study concentrates on Fat3. This fat homologue is shown to be the most widely expressed in the brain. Conditional knockout (KO) of Fat3 in brains of adult mice was attempted using the inducible Thy1Cre(ERT2) SLICK H line. Behavioral and biochemical analysis revealed that mice with conditional KO of Fat3 in the brain display no abnormalities. This may be ascribed either to the limited efficiency of the KO strategy pursued or to the lack of effect of Fat3 KO on autophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia / genetics*
  • Ataxia / metabolism
  • Autophagy
  • Brain / metabolism*
  • Cadherins / biosynthesis
  • Cadherins / deficiency
  • Cadherins / genetics*
  • Cerebellum / metabolism
  • Disease Models, Animal*
  • Down-Regulation
  • Genes, Synthetic
  • Heredodegenerative Disorders, Nervous System / genetics*
  • Heredodegenerative Disorders, Nervous System / metabolism
  • Integrases / genetics
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Myoclonic Epilepsies, Progressive / genetics*
  • Myoclonic Epilepsies, Progressive / metabolism
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics*
  • Olfactory Bulb / metabolism
  • Organ Specificity
  • Promoter Regions, Genetic / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Thy-1 Antigens / genetics

Substances

  • Cadherins
  • Fat3 protein, mouse
  • Fat4 protein, mouse
  • Nerve Tissue Proteins
  • Recombinant Fusion Proteins
  • Thy-1 Antigens
  • atrophin-1
  • fat1 protein, mouse
  • Hippo protein, mouse
  • Protein-Serine-Threonine Kinases
  • Cre recombinase
  • Integrases