Pathological TDP-43 in parkinsonism–dementia complex and amyotrophic lateral sclerosis of Guam

Abstract

Pathological TDP-43 is the major disease protein in frontotemporal lobar degeneration characterized by ubiquitin inclusions (FTLD-U) with/without motor neuron disease (MND) and in amyotrophic lateral sclerosis (ALS). As Guamanian parkinsonism-dementia complex (PDC) or Guamanian ALS (G-PDC or G-ALS) of the Chamorro population may present clinically similar to FTLD-U and ALS, TDP-43 pathology may be present in the G-PDC and G-ALS. Thus, we examined cortical or spinal cord samples from 54 Guamanian subjects for evidence of TDP-43 pathology. In addition to cortical neurofibrillary and glial tau pathology, G-PDC was associated with cortical TDP-43 positive dystrophic neurites and neuronal and glial inclusions in gray and/or white matter. Biochemical analyses showed the presence of FTLD-U-like insoluble TDP-43 in G-PDC, but not in Guam controls (G-C). Spinal cord pathology of G-PDC or G-ALS was characterized by tau positive tangles as well as TDP-43 positive inclusions in lower motor neurons and glial cells. G-C had variable tau and negligible TDP-43 pathology. These results indicate that G-PDC and G-ALS are associated with pathological TDP-43 similar to FTLD-U with/without MND as well as ALS, and that neocortical or hippocampal TDP-43 pathology distinguishes controls from disease subjects better than tau pathology. Finally, we conclude that the spectrum of TDP-43 proteinopathies should be expanded to include neurodegenerative cognitive and motor diseases, affecting the Chamorro population of Guam.

TDP-43: a novel neurodegenerative proteinopathy

“…These TDP-43 inclusions were distinct from the tau pathology in the spinal cord. Interestingly, TDP-43 pathology was also detected in cortical and limbic regions from Guam-PDC cases, inclusions that were not detected with antibodies to the tau protein [40,41]. Thus, these results support the hypothesis that ALS and FTLD-U represent a clinical spectrum of neurodegenerative disease characterized by TDP-43 pathology (Fig.…”

“…Consistent with these findings is the reported absence of TDP-43 immunoreactivity in inclusions in mutant SOD1 (G93A) transgenic mice [39]. In contrast, in Guam ALS and parkinsonism-dementia complex (PDC), a disease of unknown etiology affecting the Chamorro populations and characterized by extensive tau pathology, TDP-43 inclusions were detected in the spinal cord of both ALS and PDC cases but not in controls [40]. These TDP-43 inclusions were distinct from the tau pathology in the spinal cord.…”

“…In a related study on Lewy body disease, co-morbid TDP-43 pathology was identified in 29% of cases with Dementia with Lewy body and AD pathology, 19% of Parkinson's disease dementia, and 7% of Parkinson's disease [44]. TDP-43 pathology was also a consistent feature in affected Chamorrans with Guam-PDC, but not in controls [40,41]. Whether TDP-43 pathology represents concomitant FTLD-U pathology in these cases or is analogous to co-localization of α-synuclein pathology in AD remains to be determined.…”

Liver X receptor β (LXRβ): A link between β-sitosterol and amyotrophic lateral sclerosis–Parkinson's dementia

“…Studies have focused on the role of neurotoxicity of sterol glucosides found in the seeds of Cycas circinalis that are part of the diet in Guam (2) and on the neurotoxin ␤-methylamino-alanine found in cyanobacteria (3). The spinal cords of ALS patients are characterized by pathological accumulation of sphingomyelin, ceramides, and cholesterol esters (4), which are thought to sensitize motor neurons to programmed cell death and cytoplasmic accumulation of aggregates of ubiquitin and transactivation response DNA-binding protein (TDP-43) (5,6).…”

TDP-43 immunoreactivity in neurodegenerative disorders: disease versus mechanism specificity

“…The other school favored the idea that ALS on Guam was an independent disease process similar to ALS that occurred in other settings [18]. The relative specificity of TDP-43 has been used to study ALS than occurs on Guam in the study by Geser and co-workers in this issue of Acta Neuropathologica [7]. Spinal cord pathology was studied in a group of cases of ALS, PDC and normal controls from Guam.…”