Pallidonigral TDP-43 pathology in Perry syndrome

Parkinsonism Relat Disord. 2009 May;15(4):281-6. doi: 10.1016/j.parkreldis.2008.07.005. Epub 2008 Aug 23.


Objective: Autosomal dominant parkinsonism, hypoventilation, depression and severe weight loss (Perry syndrome) is an early-onset rapidly progressive disease. At autopsy, previous studies have found severe neuronal loss in the substantia nigra without Lewy bodies. Transactive response DNA-binding protein of 43 kDa (TDP-43) has recently been identified as a major ubiquitinated constituent of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis. This study reports clinical, genetic and neuropathologic investigations of Perry syndrome.

Methods: Clinical data and autopsy brain tissue samples were collected from eight patients from four genealogically unrelated kindreds with Perry syndrome. Brain tissue was studied with immunohistochemistry and biochemistry for TDP-43. Patients were screened for mutations in the progranulin (GRN) and TDP-43 (TARDBP) genes.

Results: The mean age at onset was 47 years (range 40-56), and the mean age at death was 52 years (range 44-64). In all patients, we identified TDP-43-positive neuronal inclusions, dystrophic neurites and axonal spheroids in a predominantly pallidonigral distribution, and we demonstrated changes in solubility and electrophoretic mobility of TDP-43 in brain tissue. The inclusions were highly pleomorphic and predominated in the extrapyramidal system, sparing the cortex, hippocampus and motor neurons. There were no mutations in GRN or TARDBP.

Interpretation: Perry syndrome displays unique TDP-43 pathology that is selective for the extrapyramidal system and spares the neocortex and motor neurons.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Depression / complications
  • Depression / genetics
  • Depression / pathology*
  • Female
  • Globus Pallidus / metabolism*
  • Humans
  • Hypoventilation / complications
  • Hypoventilation / genetics
  • Hypoventilation / pathology*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Male
  • Middle Aged
  • Parkinsonian Disorders / complications
  • Parkinsonian Disorders / genetics
  • Parkinsonian Disorders / pathology*
  • Progranulins
  • Substantia Nigra / metabolism*
  • Weight Loss*


  • DNA-Binding Proteins
  • GRN protein, human
  • Intercellular Signaling Peptides and Proteins
  • Progranulins