Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases

Department of Psychiatry and Behavioral Sciences, University of Washington Seattle, Seattle, Washington, United States
Acta Neuropathologica (Impact Factor: 10.76). 09/2007; 114(3):221-9. DOI: 10.1007/s00401-007-0261-2
Source: PubMed


Here, we investigated if TAR-DNA-binding protein-43 (TDP-43), the disease protein in frontotemporal lobar degeneration and ubiquitin inclusions with or without motor neuron disease as well as amyotrophic lateral sclerosis, also formed inclusions in Lewy body (LB) disorders including Parkinson's disease (PD) without or with dementia (PDD), and dementia with LBs (DLB) alone or in association with Alzheimer's disease (AD). Immunohistochemical analyses of TDP-43 in clinically well characterized and pathologically confirmed cases of DLB + AD, PD and PDD demonstrated TDP-43 pathology in the following percentage of cases: DLB + AD = 25/80 (31.3%); PD = 5/69 (7.2%); PDD = 4/21 (19%), while DLB and normal controls exhibited no (0/10, 0%) and one cases (1/33, 3%) presenting TDP-43 pathology, respectively. Significant differences in the prevalence of TDP-43 lesions were noted between disease versus normal brains (P < 0.001) as well as demented versus non-demented brains (P < 0.001). Statistical analyses revealed a positive relationship between TDP-43 lesions and several clinical and pathological parameters in these disorders suggesting the TDP-43 pathology may have co-morbid effects in LB diseases. This study expands the concept of TDP-43 proteinopathies by implicating TDP-43 lesions in mechanisms of neurodegeneration in LB disorders.

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    • "Previously a relatively little-studied protein, the stature of TDP- 43 has grown considerably due to description of mutations in the TARDBP gene in sporadic and familial cases of ALS and the discovery that TDP-43 is a major constituent of ubiquitin-positive inclusions in FTD and ALS (Neumann et al., 2006; Sreedharan et al., 2008). Subsequent demonstration that TDP-43 positive aggregates are found in numerous other neurodegenerative disorders including Parkinson's disease and AD have consequently raised the possibility that TDP-43 may be an intriguing therapeutic target outside of FTLD-TDP (Amador-Ortiz et al., 2007; Nakashima-Yasuda et al., 2007). TDP-43 is also one of a number of disease-related proteins with a known role in RNA metabolism (Polymenidou et al., 2011), a field that over the last decade has grown considerably in impact due to an increasing appreciation for its complexity and influence in multiple biological systems. "
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    ABSTRACT: In the search for therapeutic modifiers, frontotemporal dementia (FTD) has traditionally been overshadowed by other conditions such as Alzheimer's disease (AD). A clinically and pathologically diverse condition, FTD has been galvanized by a number of recent discoveries such as novel genetic variants in familial and sporadic forms of disease and the identification of TAR DNA binding protein of 43 kDa (TDP-43) as the defining constituent of inclusions in more than half of cases. In combination with an ever-expanding knowledge of the function and dysfunction of tau—a protein which is pathologically aggregated in the majority of the remaining cases—there exists a greater understanding of FTD than ever before. These advances may indicate potential approaches for the development of hypothetical therapeutics, but FTD remains highly complex and the roles of tau and TDP-43 in neurodegeneration are still wholly unclear. Here the challenges facing potential therapeutic strategies are discussed, which include sufficiently accurate disease diagnosis and sophisticated technology to deliver effective therapies.
    Full-text · Article · Aug 2014 · Frontiers in Aging Neuroscience
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    • "Previous research has focused on assessing TDP- 43 pathogenesis in selected clinical populations, such as FTD groups. There has been some investigation in non-demented old individuals, with prevalence of solid neuronal TDP-43 inclusions reported to vary between 0 and 30% in clinic-based samples [18] [19] [20] [21] [22] [23] and to be 46% in a community-based sample [11]. One population-based (90+ Study) study has examined the prevalence in 108 individuals [24]. "
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    ABSTRACT: Background: The significance of TDP-43 pathology in relation to aging and dementia in the population is unclear. Objective: We aimed to determine the prevalence of transactive response DNA-binding protein of 43 kDA (TDP-43) neuronal inclusions in a population-based sample, and associations with age group at death (≤90 and >90 years) and clinical dementia status prior to death. Further, we investigate associations between TDP-43 inclusions and other key dementia-related neuropathologies (plaques, tangles, and neuronal loss) within the hippocampus and entorhinal and temporal cortices. Methods: All brain donors within the Cambridge City over-75 s Cohort (CC75C), which is population-based and longitudinally tracked (n = 228), were included. Age at death ranged from 78 to 106 years. TDP-43 neuronal inclusions were assessed in the hippocampus, entorhinal cortex, and temporal cortex. These data were combined with existing clinical and neuropathological data. Results: TDP-43 neuronal inclusions were present in 27% of the sample, 36% of those with clinical dementia and 18% without dementia. Individuals who died later (>90 years) or with clinical dementia were more likely to show TDP-43 inclusions. Hippocampal and entorhinal TDP-43 inclusions were significantly associated with dementia severity and increasing age, taking into account other neuropathologies. TDP-43 neuronal inclusions appeared to co-localized with severe neuronal loss. Conclusion: Findings indicate that hippocampal and entorhinal TDP-43 inclusions are important substrates of late onset dementia which appear to co-localize with severe neuronal loss, but not with Alzheimer's disease markers of amyloid and tau. This broadens the accepted view of TDP-43 pathology in dementias.
    Full-text · Article · Jun 2014 · Journal of Alzheimer's disease: JAD
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    • "The nature of the inclusions remained largely unknown until a remarkable discovery identified the TAR DNA binding protein (TDP-43) as a major component in UBIs of ALS and also of Frontotemporal Lobar Degeneration (FTLD-TDP) [3], [4]. TDP-43 positive inclusions are present in both sporadic and familial forms of ALS and FTLD [3], [4] and have also been identified in other neurodegenerative diseases, such as, Parkinson [5], Alzheimer [6], Huntington [7] and inclusion body myopathies [8]. Although mutations in the gene encoding TDP-43, TARDBP, are relatively infrequent (<1% of total ALS cases), TDP-43 pathology is common to >90% of ALS cases, including those caused by mutations in the recently identified gene, C9orf72 [9]. "
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    ABSTRACT: Amyotrophic Lateral Sclerosis (ALS) is a devastating adult onset neurodegenerative disease affecting both upper and lower motor neurons. TDP-43, encoded by the TARDBP gene, was identified as a component of motor neuron cytoplasmic inclusions in both familial and sporadic ALS and has become a pathological signature of the disease. TDP-43 is a nuclear protein involved in RNA metabolism, however in ALS, TDP-43 is mislocalized to the cytoplasm of affected motor neurons, suggesting that disease might be caused by TDP-43 loss of function. To investigate this hypothesis, we attempted to generate a mouse conditional knockout of the Tardbp gene using the classical Cre-loxP technology. Even though heterozygote mice for the targeted allele were successfully generated, we were unable to obtain homozygotes. Here we show that although the targeting vector was specifically designed to not overlap with Tardbp adjacent genes, the homologous recombination event affected the expression of a downstream gene, Masp2. This may explain the inability to obtain homozygote mice with targeted Tardbp.
    Full-text · Article · Apr 2014 · PLoS ONE
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