Associate editor: C.N. Pope
Environmental neurotoxic chemicals-induced ubiquitin proteasome system dysfunction in the pathogenesis and progression of Parkinson's disease

https://doi.org/10.1016/j.pharmthera.2007.04.001Get rights and content

Abstract

Proteolytic degradation of unwanted proteins by the ubiquitin-proteasome system (UPS) is critical for normal maintenance of various cellular functions. Parkinson's disease (PD), one of the most prevalent neurodegenerative disorders, is characterized by prominent and irreversible nigral dopaminergic neuronal loss and intracellular protein aggregations. Epidemiological studies imply both environmental neurotoxins and genetic predisposition as potential risk factors for PD, though mechanisms underlying selective dopaminergic degeneration remain unclear. Studies with experimental PD models and postmortem PD brains have provided explicit evidence for mitochondria dysfunction and oxidative stress in PD pathogenesis. Recent identification of mutants in PINK1, DJ-1, Parkin, and LRRK-2 genes compliments the oxidative stress and mitochondrial dysfunction hypotheses in dopaminergic neuronal degeneration in PD. Mutants of α-synuclein, Uch-L1 and Parkin support the involvement of UPS dysfunction in PD. Furthermore, various Parkinsonian toxicants have been shown to impair mitochondrial function, redox balances, and to some extent protein degradation machinery. Because environmental exposure to various neurotoxic agents is considered a dominant risk for development of PD, the interrelationship between neurotoxicant exposures and UPS dysfunction must be clearly understood. Elucidation of this interrelationship will help clarify 2 areas: (i) whether UPS dysfunction in PD is a primary pathogenic factor leading to nigral neuronal death or if it simply occurs as a consequence of oxidative stress and mitochondrial dysfunction and (ii) the interaction of genes and environment in the acceleration of nigral dopaminergic degeneration by targeting UPS. We review the recent evidence for UPS deficits in dopaminergic degeneration triggered by neurotoxins.

Introduction

Parkinson's disease (PD), originally documented by James Parkinson in 1817, is the second most common neurodegenerative disorder. The disease affects over 1 million people in North America (Lang & Lozano, 1998) and 4 million worldwide (von Bohlen und Halbach et al., 2004). The neuropathological and neurochemical changes of PD are characterized by prominent loss of pigmented dopamine (DA) neurons in the substantia nigra pars compacta region, the presence of intracellular proteinaceous inclusions in the remaining DA neurons, and profound striatal DA depletion. The typical clinical symptoms of PD include bradykinesia, resting tremors, rigidity, and postural instability (Dauer & Przedborski, 2003). These major signs manifest when less than 60% of DA neurons remain in SNpc and greater than 80% loss of striatal DA (Dauer & Przedborski, 2003). Additionally, several autonomic symptoms such as salivation, constipation, loss of smell, bladder disturbances, and cardiovascular dysfunction are noted during the very early stages of PD (Magerkurth et al., 2005, Chaudhuri et al., 2006).

Etiology studies involving monozygotic and heterozygotic twins implicated a major role of environmental factors and a minor role of genetic factors in PD pathogenesis (Tanner, 2003, Warner and Schapira, 2003). The etiopathogenesis of PD, which has been researched intensively during the past several decades, is becoming increasingly understood, particularly after the finding that accidental 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP) exposure led to Parkinsonism in humans (Langston & Ballard, 1984). Subsequent studies showed that MPTP consistently produces key signs of PD in mice and nonhuman primates, which yielded critical insight into PD pathogenesis, including mitochondrial dysfunction, oxidative stress, and cell death mechanisms (Dauer and Przedborski, 2003, von Bohlen und Halbach et al., 2004, Bove et al., 2005). Several epidemiological studies showed environmental factors, such as rural living, well-water drinking, prolonged pesticide/insecticide exposure, and metal exposure, increase the risk of developing PD (Di Monte et al., 2002, Lai et al., 2002).

Toxicological studies showed that subacute exposure to the common pesticides rotenone and paraquat induces behavioral and pathological changes characteristic of PD in animal models (Dauer and Przedborski, 2003, von Bohlen und Halbach et al., 2004, Bove et al., 2005, Dinis-Oliveira et al., 2006). The positive association between environmental neurotoxicant exposure and PD indicates the important role of environmental factors in the process of nigrostriatal degeneration in PD. Clinical and toxicological studies will generate needed experimental data to determine the putative causal role of environmental dopaminergic neurotoxins in PD etiopathogenesis.

In addition to environmental factors, increased levels of extrasynaptic DA and its autooxidation products in striatum could also be detrimental to neurons, as intrastriatal injection of DA or repeated methamphetamine (inducer of DA release) administration causes degeneration of nigrostriatal projection in rodents (Bozzi & Borrelli, 2006). Due to the structural similarity to DA, 6-hydroxyl DA (6-OHDA) could be actively absorbed into catecholaminergic neurons through DA transporters (DAT) or norepinephrine transporters (NET). 6-OHDA was the first compound identified capable of eliciting selective dopaminergic neurotoxicity, which has been well characterized in rodents and nonhuman primates (Bove et al., 2005). Currently, MPTP and 6-OHDA models are commonly used for studying PD pathogenesis or for evaluating neuroprotective agents for PD (Kanthasamy & Kaul, 2006).

During the last 10 years, several gene mutations have been found to be associated with familial PD. The finding of α-synuclein mutation in familial PD has lent more support for the contribution of genetic factors to PD, especially after the finding that wild type α-synuclein is the major component of Lewy bodies in both familial and sporadic PD. Although less than 10% of PD cases are heritable, genetic information acquired from familial PD has yielded clues to the possible molecular mechanisms of PD pathogenesis. Characterization of the normal function and subcellular localization of the gene products implicate mitochondrial dysfunction/oxidative stress (PINK1, DJ-1, Parkin, and LRRK2) and ubiquitin proteasome system (UPS) impairment (Uch-L1, Parkin and α-synuclein) as key events associated with PD (Moore et al., 2005). Post-mortem analysis of PD brains and toxin-induced studies in PD models have yielded consistent and explicit evidence, supporting the pathogenic role of mitochondria dysfunction and the resulting oxidative injury, in PD (Bove et al., 2005). DA metabolism (both enzymatic and autooxidation) and mitochondrial complex I inhibition represent the 2 major processes leading to ROS generation in dopaminergic neurons; the promotion of ROS generation by the mitochondrial complex I inhibitors 1-methyl-4-phenylpyridinium ion (MPP+), rotenone, and 6-OHDA has been demonstrated to produce key features of PD in vitro and in vivo (Shen and Cookson, 2004, Bove et al., 2005). Much attention has been directed toward the role of oxidative stress in PD; however, the importance of UPS dysfunction in the pathogenesis of PD is also gaining recognition (Betarbet et al., 2005). This review summarizes the recent progress with regard to the involvement of UPS impairment in neurotoxin-induced dopaminergic degeneration in vitro and in vivo.

Section snippets

Ubiquitin-proteasome system

UPS is the principal cellular proteolysis machinery involving ubiquitin, cascades of enzymes for ubiquitination, and the proteolysis complex 26S proteasome (Glickman & Ciechanover, 2002). Numerous proteins participating in a variety of cellular processes, such as the cell cycle, signal transduction, and apoptosis, normally undergo proteolytic degradation in UPS.

Evidence from sporadic Parkinson's disease

As is the common defining feature of several neurodegenerative diseases, aggregation of misfolded proteins during neurodegeneration is evocative of deficient protein processing and degradation, although the relevance of protein aggregation to neuronal death or survival is still uncertain. As a defining pathology of PD, cytoplasmic protein aggregates, known as Lewy bodies, contain a variety of proteins including α-synuclein, ubiquitin, proteasome subunits, chaperone proteins, and neurofilament

Etiological agents involved in ubiquitin-proteasome system impairment in Parkinson's disease

Although less than 10% of PD cases are heritable, genetic information acquired from familial PD cases has yielded clues to understanding the possible molecular mechanisms of PD pathogenesis. The identified PD genes implicate defective UPS, mitochondrial dysfunction, and oxidative stress in PD pathogenesis. Mitochondrial deficit and oxidative injury have consistently been demonstrated as key features in PD pathogenesis by postmortem analysis of PD brains and experimental studies utilizing

Puzzles and future directions

Data derived from genetic and biochemical analyses have implied that a defective UPS may play a contributory role in nigrostriatal degeneration. Consistent with this idea, UPS impairment is observed in dopaminergic neurotoxicity provoked by neurotoxins including MPTP/MPP+, DA, 6-OHDA, metals, rotenone, paraquat, and dieldrin. Altered UPS function might occur as a secondary response to nigrostriatal degeneration, or it may be a key cellular event responsible for degeneration (Zeng et al., 2006).

Acknowledgments

This work was supported by National Institute of Health (NIH) grants NS45133, NS 38644, and ES10586. The authors acknowledge Ms. Keri Henderson for her assistance in the preparation of this manuscript.

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