Pathogenesis of nigral cell death in Parkinson's disease

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Abstract

Parkinson's disease (PD) is primarily a sporadic condition which results mainly from the death of dopaminergic neurons in the substantia nigra. Its etiology remains enigmatic while its pathogenesis begins to be understood as a multifactorial cascade of deleterious factors. As of yet, most insights into PD pathogenesis are derived from toxic models of PD and show that the earlier cellular perturbations arising in dopaminergic neurons include oxidative stress and energy crisis. These alterations, rather than killing neurons, trigger subsequent death-related molecular pathways including elements of apoptosis. The fate of dopaminergic neurons in PD may also be influenced by additional factors such as excitotoxicity, emanating from the increased glutamatergic input from the subthalamic nucleus to the substantia nigra, and the glial response that arises in the striatum and the substantia nigra. In rare instances, PD can be familial, and those genetic forms have also provided clues to the pathogenesis of nigrostriatal dopaminergic neuron death including abnormalities in the mechanisms of protein folding and degradation as well as mitochondrial function. Although more remains to be elucidated about the pathogenic cascade in PD, the compilation of all of the aforementioned alterations starts to shed light on why and how nigral dopaminergic neurons may degenerate in this prominent disease, that is PD.

Introduction

Parkinson's disease (PD) is the second most common neurodegenerative disorder after the Alzheimer's dementia. It is estimated that more than one million individuals in the United States of America alone are affected with this disabling disease and that more than 50,000 new cases arise each year [1]. PD is progressive with a mean age at onset of 55, and with an incidence that increases markedly with age [2]. Clinically, PD is characterized by the cardinal features of tremor at rest, slowness of voluntary movements, rigidity, and postural instability [1]. Like many other neurodegenerative diseases, PD presents itself mainly as a sporadic condition, meaning in absence of any genetic linkage, but in rare instances, PD can also arise as a simple Mendelian trait, linked to defects in a variety of genes [3]. Although, clinically and pathologically, sporadic and familial PD may differ on several significant aspects, they all share the same biochemical brain abnormality, namely a dramatic depletion in brain dopamine [2].

The reason why PD patients exhibit low levels of brain dopamine stems from the degeneration of the nigrostriatal dopaminergic pathway, which is made of dopaminergic neurons whose cell bodies are located in the substantia nigra pars compact and whose projecting axons and nerve terminals are found in the striatum [2]. Yet, it is important to emphasize the fact that the neuropathology of PD is far from being restricted to the nigrostriatal pathway, and histological abnormalities can be found in many other dopaminergic and even non-dopaminergic cell groups [2]. The second most prominent neuropathological feature of PD is the presence of intraneuronal inclusions called Lewy bodies (LBs) in the few remaining nigral dopaminergic neurons [2]. LBs are spherical eosinophilic cytoplasmic aggregates composed of a variety of proteins, such as α-synuclein, parkin, ubiquitin and neurofilaments, and they can be found in every affected brain region [2].

Over the past few decades a large core of data originating from clinical studies, autopsy materials, and in vitro and in vivo experimental models of PD has been accumulated, which led us to begin to have some level of understanding of the pathogenesis of sporadic PD [2]. Available data would argue that the mechanism of neuronal death in PD starts with an otherwise healthy dopaminergic neuron being hit by an etiological factor, such as mutant α-synuclein. Subsequent to this initial event, it is proposed that a cascade of deleterious factors is set in motion within that neuron made not of one, but rather of multiple factors such as free radicals, mitochondrial dysfunction, excitotoxicity, neuroinflammation, and apoptosis to cite only some of the most salient. Still based on this proposed scenario, all of these noxious factors will interact with each other to ultimately provoke the demise of the injured neuron.

Despite unquestionable major advances made in the molecular and cellular biology of PD and other neurodegenerative diseases which brought us closer than ever to being capable of unraveling the pathogenesis of PD, several critical questions remain unanswered. In this paper, three pending questions pertinent to the mechanisms of neuronal death in PD are discussed and form the body of this review. To be discussed first will be the question of what do we know about the nature of the pivotal factors and the sequence in which they act within the proposed pathogenic cascade that leads to neuronal death in PD. Second is the question to know whether the overall neurodegenerative process in PD is truly a cell autonomous process will be briefly addressed. Finally, one cannot avoid discussing the contribution of rare, inherited forms of PD to our current understanding of the pathogenesis of sporadic of PD.

Section snippets

Nature and sequence of action of pathogenic factors in PD

The current model of pathogenesis that most investigators in the field utilize has been outlined above. To confirm the actual role of these different presumed factors and the sequence by which they, respectively, intervene in this multifactorial cascade has been primarily, if not exclusively, studied in toxic experimental models of PD, which are numerous. Findings from these models and especially from that produced by the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Is the neurodegenerative process in PD cell autonomous?

This question is of critical importance both for pathogenic and therapeutic reasons. Indeed, it is quite important to determine whether the demise of nigral dopaminergic neurons strictly results from the cellular perturbations that arise within these neurons due to the disease's etiology, or from a complex interaction between what are called intrinsic and extrinsic perturbations. The answer to this question is complicated and far from straightforward. For instance, if one reviews the body of

Insights from the rare inherited forms of PD

Until recently, all of the hypotheses regarding the cause and the mechanisms of PD neurodegeneration came from investigations performed in autopsy material from sporadic PD cases or in neurotoxic models [2]. However, less than a decade ago this situation changed with the identification of a mutation in α-synuclein associated with PD in an Italian kindred [29]. Since then, four additional PD-causing genes have been identified, and a linkage has been reported for at least five more. Although

Conclusion

In this short review, an attempt has been made to stress the fact that the current consensus regarding the pathogenesis of sporadic PD is based primarily on information gathered from neurotoxic models of the disease. Based on these data, it appears that nigral dopaminergic neuron degeneration does not result from the action of a single deleterious factor, but rather from the convergence of multiple pathogenic factors. Many of these noxious factors emanate from within the dopaminergic neurons,

Acknowledgements

The author thanks Mr M. Lucas for assistance in preparing this manuscript. The author is supported by NIH/NINDS (grants R29 NS37345, RO1 NS38586 and NS42269, P50 NS38370, and P01 NS11766-27A1), NIH/NIA grant (RO1 AG021617-01), the US Department of Defense (DAMD 17-99-1-9474 and DAMD 17-03-1), the Lowenstein Foundation, the Lillian Goldman Charitable Trust, the Parkinson's Disease Foundation, the American Parkinson Disease Association, and MDA/Wings-Over-Wall Street.

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