Article: article from journal or magazin.
Pallidonigral TDP-43 pathology in Perry syndrome.
Parkinsonism and Related Disorders
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.
DNA-Binding Proteins/genetics, DNA-Binding Proteins/metabolism, Depression/complications, Depression/genetics, Female, Globus Pallidus/metabolism, Humans, Hypoventilation/complications, Hypoventilation/genetics, Intercellular Signaling Peptides and Proteins/genetics, Male, Middle Aged, Parkinsonian Disorders/complications, Parkinsonian Disorders/genetics, Substantia Nigra/metabolism, Weight Loss
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