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

Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, HUP/Maloney 3rd Floor, Philadelphia, PA 19104-4283, USA.
Acta Neuropathologica (Impact Factor: 9.78). 09/2007; 114(3):221-9. DOI: 10.1007/s00401-007-0261-2
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ABSTRACT 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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