Sci. Aging Knowl. Environ., 1 December 2004
Vol. 2004, Issue 48, p. pe42
[DOI: 10.1126/sageke.2004.48.pe42]

PERSPECTIVES

Mitochondrial Injury: A Hot Spot for Parkinsonism and Parkinson's Disease?

Benoit I. Giasson

The author is in the Department of Pharmacology at the University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA. E-mail: giassonb{at}mail.med.upenn.edu

http://sageke.sciencemag.org/cgi/content/full/2004/48/pe42

Key Words: Parkinson's disease • Mitochondria • {alpha}-synuclein • parkin • E3 ligase • DJ-1 • PINK1

Introduction

Parkinson's disease (PD) is a progressive neurodegenerative disease that affects ~1% of the population by 65 years of age and about 4 to 5% of the population by 85 years of age. The main clinical characteristics of PD include bradykinesia (slow movement), resting tremor, cogwheel rigidity (intermittent and jerky resistance to passive movement), and postural instability (1). The major disabling symptoms of PD are predominantly due to the profound loss of dopamine-releasing neurons in a tiny section of the brain near the brain stem called the substantial nigra pars compacta (SNpc) (2, 3). Dopamine is a neurotransmitter involved in stimulating and coordinating the body's motor movements. Treatment with levodopa, the precursor of dopamine, has been an effective therapy to ameliorate some symptoms, and responsiveness to levodopa is used as a diagnostic indicator of PD (see Andersen Review). In addition to extensive loss of dopaminergic neurons in the SNpc, the presence of intracytoplasmic protein-containing inclusions called Lewy bodies (LBs) distinguishes PD from other disorders that present with clinical parkinsonism (4, 5) (see Thal Perspective).

{alpha}-Synuclein Mutations and Pathological Inclusions in PD

The identification of a specific point missense mutation in the {alpha}-synuclein gene (resulting in an Ala53->Thr53 change) in kindreds with PD, followed by a multitude of histological and biochemical studies, have demonstrated that {alpha}-synuclein molecules are the primary building blocks of the ~10-nm fibrils that form LBs (6, 7) (see Berezovska Perspective). Although {alpha}-synuclein is normally a soluble monomeric presynaptic protein, it can be triggered to polymerize into insoluble fibrils (6). This polymerization is associated with a dramatic conformational change from a random coil to a {beta}-pleated sheet (8, 9).

Evidence from in vitro studies, transgenic Drosophila and mouse models, and the analysis of autopsy specimens indicates that the aberrant polymerization of {alpha}-synuclein into filaments, which eventually form large intracytoplasmic inclusions in cell bodies and processes, can lead to the dysfunction and demise of neurons and/or oligodendrocytes (cells that help insulate neurons) (6, 10) (see "Murder on the Parkinson's Express" and "A Clique's Undoing"). For example, transgenic mice that express the Ala53->Thr53 mutant form of human {alpha}-synuclein in their neurons develop a severe age-dependent motor disability associated with the formation of {alpha}-synuclein cytoplasmic pathological inclusions (11). These aggregates appear to create physical blocks that obstruct normal cellular trafficking and disrupt cell morphology (see "Stuck in the Craw"). Although the preponderance of evidence supports the idea that {alpha}-synuclein toxicity is linked to the formation of pathological inclusions, studies by Lansbury et al. [reviewed in (12)] indicate that {alpha}-synuclein protofibrils might also be toxic by making the cell membrane more porous. These two alternative hypotheses are not mutually exclusive, however, and both argue for a toxic role of {alpha}-synuclein aggregation in disease. (See also the Trojanowski Perspective and Lee Perspective, which describe recent findings about the genetics and cell biology of PD.)

Environmental Toxins Link Mitochondrial Dysfunction to Parkinsonism

The findings that the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can cause parkinsonian motor dysfunction in humans, monkeys, and rodents suggest that mitochondrial impairment might be involved in PD (13) (see Ogawa Perspective and "The Two Faces of Oxygen" ). The mode of action of this toxin likely involves the selective uptake of its metabolite, the 1-methyl-4-phenylpyridinium ion (MPP+), by the plasma membrane dopamine transporter. Once MPP+ enters dopaminergic neurons, it inhibits mitochondrial complex I (the first enzyme complex in the electron transport chain) and may have other effects on dopamine metabolism (see Nicholls Perspective). {alpha}-synuclein pathological inclusions are not present in rodents, human, or monkeys exposed to MPTP (14). Therefore, the selective toxicity of MPTP appears to be due to its specific pharmacological properties and does not directly demonstrate that mitochondrial impairment is involved in classical PD.

Perhaps the best evidence for the possible role of mitochondrial injury in causing PD comes from an experimental animal model in which rats are treated with rotenone (15). Rotenone is a pesticide and, similar to like MPP+, it is an inhibitor of mitochondrial complex I. Rats exposed to this toxin develop many symptoms that closely parallel those seen in PD patients, including bradykinesia, posture instability, and an unsteady gait. Moreover, the nigrostriatal dopaminergic system undergoes significant degeneration, and some surviving dopaminergic neurons develop intracytoplasmic {alpha}-synuclein-rich inclusions that resemble LBs when visualized by light and electron microscopy. Some of these inclusions have a distinct core surrounded by a fibrillar halo, similar to authentic human LBs.

Recessive Genetic Mutations Point to Mitochondrial Impairment in PD

As much as 50% of patients with early-onset (<40 years of age) parkinsonism harbor mutations in the parkin gene (also knows as PARK2), and a range of nonsense, missense, and insertion/deletion mutations have been shown to cause a form of PD called autosomal recessive juvenile parkinsonism (AR-JP) (16-18) (see "Death Be Not Degrading"). Patients with parkin mutations exhibit the typical clinical features of parkinsonism and are markedly responsive to levodopa therapy. Neuropathological examination of their brain tissues shows neuronal loss and gliosis in the midbrain, but {alpha}-synuclein pathological inclusions (LBs) are typically not observed.

The parkin gene encodes a 465-amino acid enzyme (an E3 ligase) that normally helps tag cellular proteins with a molecule called ubiquitin, which marks them for destruction by the proteasome (19-23) (see Gray Review, "Dumpster Diving", and "Deadly Giveaway"). Several findings suggest that parkin may also play an important role in maintaining mitochondrial integrity. Darios et al. (24) showed that increased parkin expression in cultured cells can protect against cell death mediated by the lipid molecule ceramide. Parkin appears to act by delaying the mitochondrial swelling and rupture of the outer mitochondrial membrane caused by ceramide, and the subsequent release of cytochrome c (an event that is a precursor to cell death). Other insights have come from studies of parkin-deficient Drosophila (25, 26). These fruit flies are viable but sterile, have defective mitochondria, exhibit reduced longevity, and are unable to fly and climb because of the degeneration of their indirect flight muscles. Loss of dopaminergic neurons has not been observed in these flies, but one study reported shrinkage of dopaminergic neurons in the dorsomedial clusters (25). Ablation of the parkin gene in mice does not cause any overt phenotype, loss of dopaminergic neurons (27), change in the total number of mitochondria, or changes in mitochondrial morphology. However, parkin-deficient mice do have decreased abundance of proteins involved in mitochondrial function, especially complexes I and IV, and demonstrate a delayed rate of weight gain consistent with broad metabolic abnormalities and reduced mitochondrial function (28).

Another locus (PARK7) found to be responsible for autosomal parkinsonism contains the gene for DJ-1 (29), a small 189-amino acid protein that exists in vivo as a dimer (30-34). The first PARK7 kindred identified had a homozygous deletion of a large region within the DJ-1 gene (encompassing the promoter and first five exons) that resulted in complete loss of DJ-1 expression (29). In addition, several homozygous point mutations in DJ-1 [causing Leu166->Pro166 (L166P), Glu64->Asp64, and Met26->Ile26 changes] have been identified in families with an autosomal PD-like disorder (29, 35, 36), and the L166P mutation has been shown to prevent the dimerization of DJ-1, resulting in its rapid degradation (36-38). Although the loss of DJ-1 can cause parkinsonism, the distribution of neuronal loss and the presence of {alpha}-synuclein pathological inclusions in affected patients have not been investigated.

The function of DJ-1 remains mostly unknown, but it has some ability to protect against oxidative stress (39). Furthermore, the exposure of cultured cells to oxidative challenges results in the oxidation of DJ-1, as seen by a shift in its isoelectric property, suggesting that it may act as a sensor of oxidative stress (40). Cys106 in DJ-1 has been identified as a residue that is prone to be oxidized to sulfinic acid, and this modification can cause relocalization of DJ-1 to the cytoplasmic side of mitochondria (41). This association of DJ-1 with the mitochondria has been shown to confer protection against some toxins such as MPP+ (41), but the mechanism is unclear.

Finally, mutations in a gene that encodes the putative mitochondrial protein kinase PINK1 (PTEN-induced kinase 1) were recently shown to be responsible for some kindreds with an autosomal recessive form of parkinsonism (42, 43). This gene (also known as PARK6) is located on chromosome 1p35-p36. Homozygous nonsense [Trp437->X437 (where X is any amino acid) and Arg246->X246] and missense mutations (Gly309->Ala309, His271->Gln271, Glu417->Gly417, and Leu347->Pro347), as well as compound nonsense mutations (Gln239->X239/Arg492->X492) have been linked to the disease, but autopsies have not been performed to determine the extent of neurodegeneration or the presence of proteinaceous inclusions in the affected tissues. Key issues about the function of PINK1 and its intracellular distribution remain to be addressed. It has been characterized as a putative serine/threonine protein kinase based on homology, but this identity has not been directly demonstrated, and possible substrates are unknown. And although PINK1 has a mitochondrial localization sequence and has been shown to be targeted to the mitochondria (42), it is possible that it functions in the cytoplasm. Nevertheless, all PINK1 disease-causing mutations identified thus far are predicted to disrupt the putative kinase domain, and it has been suggested that PINK1 may protect neurons against stress-induced mitochondrial dysfunction and apoptosis (42).

Mitochondrial Injury and {alpha}-Synuclein Aggregation: Accomplices or Separate Perpetrators?

One can envision several models for the interactions of gene products and mechanisms implicated in the demise of dopaminergic neurons (Fig. 1). Although there are some data to support interactions between DJ-1, PINK1, parkin, {alpha}-synuclein, and mitochondrial damage, the models remain speculative. Alterations in the function of these activities converge to harm dopaminergic neurons; however, they may represent parallel pathways that only converge at this final outcome. Alternatively, they may directly interact mechanistically, leading to pathogenesis. The commonality linking loss of DJ-1, PINK1, and parkin function could be the failure of mitochondrial integrity, but this could occur independently of {alpha}-synuclein aggregation, like MPTP toxicity. Postmortem studies of patients with DJ-1 and PINK1 gene defects will be important in addressing these issues. Further studies of the function of DJ-1 and PINK1 are also critical. Although oxidized DJ-1 can associate with mitochondria, the role of DJ-1 at this location as well as the mechanisms of how this protein might protect against mitochondrial injury are unclear. From the postmortem analysis of patients with AR-JP, it appears that the complete loss of parkin activity is sufficient for the degeneration of the dopaminergic nigrostriatal pathway without the involvement of {alpha}-synuclein aggregation. However, partial loss of parkin activity also may play a role in modulating biological pathways that lead to {alpha}-synuclein aggregation typical of PD (44).



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Fig. 1. Mitochondrial impairment may play a central role in PD. The pathways involving DJ-1, PINK1, and parkin that lead to neuronal demise are not well defined, but recent studies indicate that all three proteins have protective effects on the mitochondria. Direct effects of DJ-1 and PINK1 on {alpha}-synuclein polymerization have not yet been investigated. Parkin is an E3 ligase that normally promotes the degradation of toxic proteins; the accumulation of some of these substrates due to the loss of function of parkin may be sufficient for neuronal loss and could have an adverse affect on mitochondrial integrity. The presence of {alpha}-synuclein aggregates also may promote mitochondrial deficit. Conversely, impairment of mitochondrial electron chain activity can result in increased production of free radicals, which may in turn enhance the formation of {alpha}-synuclein inclusions.

 
{alpha}-synuclein aggregation is an important pathological mechanism in PD, and there is evidence to suggest that mitochondria impairment can promote {alpha}-synuclein aggregation. Patients with sporadic PD show a reduction in mitochondria complex I activity in the SN (45). Furthermore, cybrids (mitochondria-deficient cells repopulated with mitochondria derived from platelets from PD patients and controls) generated from PD patients show reduced complex I activity as compared to controls (46) and PD cybrids generated using neuroblastoma cells tend to accumulate {alpha}-synuclein inclusions (47). Impaired mitochondria electron chain transfer can lead to increased production of free radicals (see Kristal Perspective), and this oxidative stress may promote {alpha}-synuclein aggregation, similar to the finding in rats treated with rotenone (15). In line with these findings, studies in cultured cells indicate that partial mitochondria inhibition can induce {alpha}-synuclein aggregation (48, 49). It has also been suggested that {alpha}-synuclein aggregation can lead to mitochondria deficit (50). It is therefore possible that a positive and deleterious feedback loop may be induced in some situations, once mitochondrial dysfunction is initiated.

Although it is possible that the factors implicated in causing parkinsonism are mechanistically related, it is also possible that independent pathological mechanisms can lead to disease with similar clinical presentations. A better understanding of the proteins involved and of the causes and effects of mitochondrial dysfunction will hopefully lead to the identification of new therapeutic targets for the treatment and prevention of PD.


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Citation: B. I. Giasson, Mitochondrial Injury: A Hot Spot for Parkinsonism and Parkinson's Disease? Sci. Aging Knowl. Environ. 2004 (48), pe42 (2004).




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