Pallidonigral TDP-43 pathology in Perry syndrome

Christian Wider, Dennis W Dickson, A. Jon Stoessl, Yoshio Tsuboi, Françoise Chapon, Ludwig Gutmann, Bernard Lechevalier, Donald B. Calne, David A. Personett, Mary Hulihan, Jennifer Kachergus, Rosa V Rademakers, Matthew C. Baker, Linda L. Grantier, O. K. Sujith, Laura Brown, Susan Calne, Matthew J. Farrer, Zbigniew K Wszolek

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)281-286
Number of pages6
JournalParkinsonism and Related Disorders
Volume15
Issue number4
DOIs
StatePublished - May 2009

Fingerprint

Pathology
Motor Neurons
Autopsy
Brain
Lewy Bodies
Hypoventilation
Frontotemporal Dementia
Mutation
Neocortex
Amyotrophic Lateral Sclerosis
DNA-Binding Proteins
Parkinsonian Disorders
Neurites
Substantia Nigra
Age of Onset
Neuroglia
Biochemistry
Solubility
Weight Loss
Hippocampus

Keywords

  • Autosomal dominant
  • Axonal dystrophy
  • Neuronal cytoplasmic inclusions
  • Pallidonigral
  • Parkinsonism
  • Perry syndrome
  • TARDBP
  • TDP-43

ASJC Scopus subject areas

  • Geriatrics and Gerontology
  • Clinical Neurology
  • Neurology

Cite this

Pallidonigral TDP-43 pathology in Perry syndrome. / Wider, Christian; Dickson, Dennis W; Stoessl, A. Jon; Tsuboi, Yoshio; Chapon, Françoise; Gutmann, Ludwig; Lechevalier, Bernard; Calne, Donald B.; Personett, David A.; Hulihan, Mary; Kachergus, Jennifer; Rademakers, Rosa V; Baker, Matthew C.; Grantier, Linda L.; Sujith, O. K.; Brown, Laura; Calne, Susan; Farrer, Matthew J.; Wszolek, Zbigniew K.

In: Parkinsonism and Related Disorders, Vol. 15, No. 4, 05.2009, p. 281-286.

Research output: Contribution to journalArticle

Wider, C, Dickson, DW, Stoessl, AJ, Tsuboi, Y, Chapon, F, Gutmann, L, Lechevalier, B, Calne, DB, Personett, DA, Hulihan, M, Kachergus, J, Rademakers, RV, Baker, MC, Grantier, LL, Sujith, OK, Brown, L, Calne, S, Farrer, MJ & Wszolek, ZK 2009, 'Pallidonigral TDP-43 pathology in Perry syndrome', Parkinsonism and Related Disorders, vol. 15, no. 4, pp. 281-286. https://doi.org/10.1016/j.parkreldis.2008.07.005
Wider, Christian ; Dickson, Dennis W ; Stoessl, A. Jon ; Tsuboi, Yoshio ; Chapon, Françoise ; Gutmann, Ludwig ; Lechevalier, Bernard ; Calne, Donald B. ; Personett, David A. ; Hulihan, Mary ; Kachergus, Jennifer ; Rademakers, Rosa V ; Baker, Matthew C. ; Grantier, Linda L. ; Sujith, O. K. ; Brown, Laura ; Calne, Susan ; Farrer, Matthew J. ; Wszolek, Zbigniew K. / Pallidonigral TDP-43 pathology in Perry syndrome. In: Parkinsonism and Related Disorders. 2009 ; Vol. 15, No. 4. pp. 281-286.
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AU - Wider, Christian

AU - Dickson, Dennis W

AU - Stoessl, A. Jon

AU - Tsuboi, Yoshio

AU - Chapon, Françoise

AU - Gutmann, Ludwig

AU - Lechevalier, Bernard

AU - Calne, Donald B.

AU - Personett, David A.

AU - Hulihan, Mary

AU - Kachergus, Jennifer

AU - Rademakers, Rosa V

AU - Baker, Matthew C.

AU - Grantier, Linda L.

AU - Sujith, O. K.

AU - Brown, Laura

AU - Calne, Susan

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AU - Wszolek, Zbigniew K

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N2 - 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.

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KW - Neuronal cytoplasmic inclusions

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