Elsevier

Brain Research

Volume 775, Issues 1–2, 14 November 1997, Pages 24-29
Brain Research

Research report
Contribution of somal Lewy bodies to neuronal death

https://doi.org/10.1016/S0006-8993(97)00874-3Get rights and content

Abstract

Neuronal degeneration occurs in the substantia nigra pars compacta (SNpc) of patients with Parkinson's disease and other Lewy body-associated disorders. Lewy bodies (LBs) are abnormal inclusions found in the SNpc and other neurons of these patients. It is not known what role LBs play in the disease process; they may be harmful to the neuron or simply an epiphenomenon of the disease process. We have previously shown that some of the neuronal death occurring in the SNpc of Lewy body-associated disorders resembles apoptosis. The present study was undertaken to determine whether apoptotic-like changes were more common in SNpc neurons with somal LBs compared to those without somal LBs. Substantia nigra from cases of Lewy body-associated disorders were labeled to colocalize apoptotic-like changes and LBs using in situ end-labeling and an anti-ubiquitin antibody. Three cases demonstrated that SNpc neurons with LBs in the perikarya had the same proportion of apoptotic-like changes as SNpc neurons without somal LBs. One case had no LB-containing SNpc neurons undergoing apoptotic-like cell death. The majority of SNpc neurons undergoing apoptotic-like cell death did not appear to contain somal LBs and thus may be dying before LB formation can occur. These results support the theory that the presence of a somal LB does not predispose a neuron to undergo apoptotic-like cell death.

Introduction

Parkinson's disease and other Lewy body-associated disorders are characterized neuropathologically by the presence of LBs in the SNpc, as well as in other brainstem, cortical and peripheral nervous system sites [8]. Lewy bodies are eosinophilic inclusion bodies occurring in the cell body, axons and dendrites of neurons, which appear to be composed mainly of neurofilaments that may be inappropriately phosphorylated, proteolytically truncated and ubiquinated (reviewed in 17, 30). Advanced glycation end-products, which are potentiated by oxidative stress, have also been described in LBs [5]. Thus LBs may be correlated with pathological changes in the cell.

Apoptosis is a type of cell death with specific morphological and biochemical distinctions (reviewed in [4]). Morphological changes include nuclear and cytoplasmic condensation, formation of membrane-bound apoptotic bodies variably containing organelles and chromatin in condensed cytoplasm, and subsequent phagocytosis by surrounding cells, including macrophages or microglia. DNA undergoes specific endonucleolytic cleavage during apoptosis 2, 39, leaving free 3′-hydroxyl ends that can be detected using an in situ end-labeling technique (ISEL) 12, 37.

The death of neurons by apoptosis or an apoptotic-like process has been recently described in several neurodegenerative disorders, including Lewy body-associated disorders (Parkinson's disease (PD), concomitant Alzheimer/Parkinson's disease (AD/PD) and diffuse Lewy body disease (DLBD) 1, 34), Alzheimer's disease (AD) 12, 23, 32, amyotrophic lateral sclerosis (ALS) 7, 36, 43and Huntington's chorea 7, 31, although other studies have not seen evidence of apoptosis in AD [26], ALS [26]and PD [7]. Apoptosis in culture and in developmental systems have specific molecular cascades [4]which as yet have not been described in human postmortem tissue; we have therefore described the morphological changes resembling apoptosis as `apoptotic-like changes'.

There is some evidence that neuropathological inclusions may affect the rate of cell death. For example, Alzheimer neurofibrillary tangles, like LBs, are cytoskeletal accumulations which are abnormally phosphorylated and ubiquinated. They are composed of the A68 phosphorylated form of the microtubule-associated protein tau [24]. Neurons with and without neurofibrillary tangles have been shown to undergo apoptosis in AD 12, 23; one study [23]showed tangle-bearing neurons to be three times more likely to undergo apoptotic cell death than neurons without tangles.

It is not known whether LBs have deleterious effects on the cells containing them. As LBs are composed of abnormal neurofilaments, their presence may indicate a general aberration of the cytoskeleton, and could directly contribute to the death of SNpc neurons [17]. Alternatively, LBs may occur as an epiphenomenon of the primary pathology and have little or no effect on neuronal death. We have previously shown that many SNpc neurons die by an apoptotic-like process in patients with Lewy body-associated disorders. In the present study, we address the question of whether the presence of a somal LB correlates with increased apoptotic-like cell death, by examining the occurrence of apoptotic-like changes in SNpc neurons with and without somal LBs.

Section snippets

Human tissue

The McLean Hospital Brain Tissue Resource Center at Harvard Medical School (Boston, MA) provided archival human tissue. Cases of concomitant AD/PD met standard neuropathological criteria for both diseases, and are likely to be classified as the Lewy body variant of Alzheimer's disease by current standards at McLean Hospital (Dr. Jean P. Vonsattel, personal communication, and [34]). DLBD cases did not meet the consensus criteria for AD, but demonstrated extensive cortical LBs and subcortical

Results

In situ end-labeling of AD/PD and DLBD cases demonstrated apoptotic-like changes in LB-containing SNpc neurons (Fig. 1). SNpc neurons and their remnants can be unequivocally identified by the presence of neuromelanin. In contrast to a normal euchromatic nucleus (Fig. 1A), SNpc nuclei undergoing early apoptotic-like changes were ISEL+ and condensed (Fig. 1C–H). We have defined early apoptotic-like changes as those ISEL+ neurons having an intact cell body (Fig. 1C–H). LB-containing neurons can

Discussion

Apoptotic-like changes have recently been described in the SNpc of PD, AD/PD and DLBD cases, using ISEL and ultrastructural analysis 1, 34. The current study employed anti-ubiquitin immunohistochemistry in conjunction with ISEL to show that some of the SNpc neurons undergoing apoptotic-like changes contained somal LBs, while many did not. However, SNpc neurons without somal LBs may contain dendritic or axonal LBs (9, 10, 25, 40, 41, Hill, unpublished observations), which could be harmful or

Acknowledgements

We thank Dr. Theresa Harrison for critical review of the manuscript and Drs. Edward D. Bird, Jean P. Vonsattel and Ms. Lisa A. Kanaley of the Brain Tissue Resource Center of McLean Hospital, Harvard Medical School, for brain tissue, as well as the donors and their families. Supported by National Institutes of Health Grant NS32835 (W.D.H.), Medical College of Georgia Research Institute Grant 2004-66 (W.D.H.), Fraternal Order of Eagles Golden Eagle Fund Grant (W.D.H.), and Public Health Service

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