Pallidonigral TDP-43 pathology in Perry syndrome

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 DNAbinding 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.

DCTN1-related neurodegeneration: Perry syndrome and beyond

“…Neurons with focal clearing of cytoplasm or eosinophilic intranuclear inclusions have been reported, but the significance of these findings are unknown [7, 9]. A variable degree of neuronal loss and gliosis is also evident in the caudate nucleus, globus pallidus, subthalamic nucleus, hypothalamus, locus ceruleus, periaqueductal gray matter, ventrolateral medulla, dorsal raphe nucleus, and pontine reticular formation [27]. From an immunohistochemistry analysis of a single autopsied case from a Japanese (Fukuoka 1) family, neuronal loss in the pre-Bötzinger complex of the ventrolateral medulla and serotonergic neuronal loss in the medullary raphe and ventrolateral medulla were found [28].…”

“…Shortly before identifying the causative gene, PS was discovered to be a transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy [27]. Based on our neuropathological analysis of eight patients with PS from Canadian (British Columbia), American (West Virginia), French, and Japanese (Fukuoka 1) families, abnormal TDP-43-positive neuronal cytoplasmic inclusions, dystrophic neurites, glial cytoplasmic inclusions, and axonal spheroids were identified mostly in the substantia nigra and the globus pallidus [5, 16, 27].…”

RNA-binding proteins as molecular links between cancer and neurodegeneration

“…Alterations in TDP-43 metabolism are not however limited to FTD and ALS. Both glial and neuronal cytoplasmic inclusions, as well as neuronal nuclear inclusions (NNIs) immunoreactive to antibodies recognizing TDP-43 have been observed in AD (Amador-Ortiz et al 2007;Higashi et al 2007;Hu et al 2008b;Uryu et al 2008), Pick disease (Freeman et al 2008), dementia with Lewy bodies (Higashi et al 2007) and various forms of PD (Farrer et al 2009;Geser et al 2008;Hasegawa et al 2007;Maekawa et al 2009;Miklossy et al 2008;Nakashima-Yasuda et al 2007;Wider et al 2009). …”

Frontotemporal Lobar Degeneration

“…Other disorders with TDP-43 pathology were reported in Perry Syndrome (Wider, Dickson et al 2009), Guamanian ALS-parkinsonism-dementia complex (Hasegawa, Arai et al 2007), but also in some cases of Alzheimer's disease and dementia with Lewy bodies (Arai, Mackenzie et al 200;Higashi, Iseki et al 2007). TDP-43 has not been described in inclusion bodies in Parkinson's disease so far.…”