Neuronal RNA oxidation is a prominent feature of dementia with Lewy bodies

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Abstract

An approach was used to identify the oxidized nucleoside, 8-hydroxyguanosine in brains of dementia with Lewy bodies. Neurons with marked immunoreaction of 8-hydroxyguanosine in the cytoplasm were widely distributed in the hippocampal region and temporal neocortex. Relative intensity measurements of neuronal 8-hydroxyguanosine immunoreactivity showed that there was a significant increase in nucleic acid oxidation in dementia with Lewy bodies compared with controls. Treatment with nuclease (DNase or RNase) before the immunostaining demonstrated that RNA was a major site of nucleic acid oxidation. Together with the previously reported RNA oxidation in vulnerable neurons in Alzheimer and Parkinson diseases, neuronal RNA oxidation in dementia with Lewy bodies might represent one of the fundamental abnormalities in age-associated neurodegenerative diseases.

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Most cited references 9

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Parkinson's disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons.

Jing Zhang, Mark A Smith, David G. Robertson … (1999)

Oxidative damage, including modification of nucleic acids, may contribute to dopaminergic neurodegeneration in the substantia nigra (SN) of patients with Parkinson's disease (PD). To investigate the extent and distribution of nucleic acid oxidative damage in these vulnerable dopaminergic neurons, we immunohistochemically characterized a common product of nucleic acid oxidation, 8-hydroxyguanosine (8OHG). In PD patients, cytoplasmic 8OHG immunoreactivity was intense in neurons of the SN, and present to a lesser extent in neurons of the nucleus raphe dorsalis and oculomotor nucleus, and occasionally in glia. The proportion of 8OHG immunoreactive SN neurons was significantly greater in PD patients compared to age-matched controls. Midbrain sections from patients with multiple system atrophy-Parkinsonian type (MSA-P) and dementia with Lewy bodies (DLB) also were examined. These showed increased cytoplasmic 8OHG immunoreactivity in SN neurons in both MSA-P and DLB compared to controls; however, the proportion of positive neurons was significantly less than in PD patients. The regional distribution of 8OHG immunoreactive neurons within the SN corresponded to the distribution of neurodegeneration for these three diseases. Nuclear 8OHG immunoreactivity was not observed in any individual. The type of cytoplasmic nucleic acid responsible for 8OHG immunoreactivity was analyzed by preincubating midbrain sections from PD patients with RNase, DNase, or both enzymes. 8OHG immunoreactivity was substantially diminished by either RNase or DNase, and completely ablated by both enzymes. These results suggest that oxidative damage to cytoplasmic nucleic acid is selectively increased in midbrain, especially the SN, of PD patients and much less so in MSA-P and DLB patients. Moreover, oxidative damage to nucleic acid is largely restricted to cytoplasm with both RNA and mitochondrial DNA as targets.

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Neuropathology of immunohistochemically identified brainstem neurons in Parkinson's disease.

W Blessing, P Howe, G Halliday … (1990)

Regional loss of immunohistochemically identified neurons in serial sections through the brainstem of 4 patients with idiopathic Parkinson's disease was compared with equivalent sections from 4 age-matched control subjects. In the Parkinson brains, the catecholamine cell groups of the midbrain, pons, and medulla showed variable neuropathological changes. All dopaminergic nuclei were variably affected, but were most severely affected in the caudal, central substantia nigra. The pontine noradrenergic locus ceruleus showed variable degrees of degeneration. There was also a substantial loss of substance P-containing neurons in the pedunculopontine tegmental nucleus. However, the most severely affected cell group in the pons was the serotonin-synthesizing neurons in the median raphe. In the medulla, substantial neuronal loss was found in several diverse cell groups including the adrenaline-synthesizing and neuropeptide Y-containing neurons in the rostral ventrolateral medulla, the serotonin-synthesizing neurons in the raphe obscurus nucleus, the substance P-containing neurons in the lateral reticular formation, as well as the substance P-containing neurons in the dorsal motor vagal nucleus. Lewy bodies were present in immunohistochemically identified neurons in many of these regions, indicating that they were affected directly by the disease process. These widespread but region- and transmitter-specific changes help account for the diversity of motor, cognitive, and autonomic manifestations of Parkinson's disease.

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Glycoxidation and oxidative stress in Parkinson disease and diffuse Lewy body disease.

R Castellani, M A Smith, P L Richey … (1996)

Oxidative stress is well accepted as an important pathogenic factor in Parkinson disease, based largely on indirect evidence. Recently, we have developed antibodies that recognize specific advanced glycation end-products (anti-pentosidine and anti-pyrraline), protein modifications that are potentiated by oxidative stress in a process termed glycoxidation. We applied these antibodies immunocytochemically to affected regions in Parkinson disease and diffuse Lewy body disease brains. Additionally, we used antibodies to heme oxygenase-1, a putative marker of oxidative stress response. Immunoreactivity to pentosidine, pyrraline, and heme oxygenase-1 was seen in the substantia nigra of Parkinson disease and the neocortex of diffuse Lewy body disease. Heme oxygenase-1 was further demonstrated by immunoelectron microscopy in intimate association with filaments of cortical Lewy bodies. Immunolocalization of advanced glycation end-products and a marker of oxidative stress response induction provides evidence that glycoxidation and oxidative stress may be an important pathogenic factor in diseases characterized by Lewy body formation, and furthers the evidence that cytoskeletal proteins and their inclusions are susceptible to oxidative stress.

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Author and article information

Journal

Title: NeuroReport

Abbreviated Title: NeuroReport

Publisher: Ovid Technologies (Wolters Kluwer Health)

ISSN (Print): 0959-4965

Publication date Created: 2002

Publication date (Print): November 2002

Volume: 13

Issue: 16

Pages: 2035-2039

Article

DOI: 10.1097/00001756-200211150-00009

PubMed ID: 12438921

SO-VID: 7840a8f6-5a47-4c4e-9489-4c9ffe72e266

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Neuronal RNA oxidation is a prominent feature of dementia with Lewy bodies :

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Abstract

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Neuronal Signaling

Most cited references 9

Parkinson's disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons.

Neuropathology of immunohistochemically identified brainstem neurons in Parkinson's disease.

Glycoxidation and oxidative stress in Parkinson disease and diffuse Lewy body disease.

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