FKBP12-immunopositive inclusions in patients with α-synucleinopathies

Brain Res. 2018 Feb 1;1680:39-45. doi: 10.1016/j.brainres.2017.12.012. Epub 2017 Dec 12.

Abstract

α-Synuclein (α-SYN), a presynaptic protein with the tendency to aggregate, is linked to α-synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). α-SYN is the main component of round intracytoplasmic inclusions called Lewy bodies (LBs), which are the hallmark of PD and DLB. In addition, accumulation of amyloid-β and neurofibrillary tangles as in the pathology of Alzheimer's disease has been found in the DLB brain. Glial cytoplasmic inclusions are an MSA-specific type of inclusion found in oligodendrocytes and mainly comprise α-SYN. FK506-binding protein (FKBP) 12 is a member of the immunophilin family with peptidyl-prolyl isomerase activity that promotes protein folding and is believed to act as a chaperone protein. Previous in vitro work indicated that FKBP12 accelerated α-SYN aggregation more than other peptidyl-prolyl isomerases. The enzymatic activity of FKBP12 increases the formation of α-SYN fibrils at subnanomolar concentrations. In this study, we found that FKBP12 colocalized with α-SYN in LBs and neurites in PD and DLB brains. Furthermore, FKBP12-immunopositive neurofibrillary tangles colocalized with phosphorylated tau in DLB and FKBP12-immunopositive glial cytoplasmic inclusions colocalized with α-SYN in MSA. These findings suggest that FKBP12 is linked to the accumulation of α-SYN and phosphorylated tau protein in α-synucleinopathies. FKBP12 may play important roles in the pathogenesis of α-synucleinopathies through its strong aggregation function. Thus, FKBP12 could be an important drug target for α-synucleinopathies.

Keywords: Dementia with Lewy bodies; FK506-binding protein 12; Lewy body; Multiple system atrophy; Parkinson’s disease; α-Synuclein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Brain / metabolism*
  • Female
  • Humans
  • Lewy Body Disease / pathology*
  • Male
  • Middle Aged
  • Multiple System Atrophy / pathology*
  • Neurites / pathology
  • Neurofibrillary Tangles / pathology
  • Parkinson Disease / pathology*
  • Tacrolimus Binding Protein 1A / metabolism*
  • alpha-Synuclein / metabolism*

Substances

  • alpha-Synuclein
  • Tacrolimus Binding Protein 1A