J. William Langston

Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyrine (MPTP) in the squirrel monkey

1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) was administered via the intraperitoneal route to squirrel monkeys. Akinesia, rigidity and hypophonia were seen after repeated doses of 2 mg/kg. Postural tremor was present in one animal. Neuropathologic examination revealed cell loss restricted to the zona compacta of the substantia nigra. MPTP appears effective in producing an animal model for Parkinsons disease in the squirrel monkey, and may be one of the more selective neurotoxins described to date.

Environmental risk factors and Parkinson's disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat.

Environmental toxicants and, in particular, pesticides have been implicated as risk factors in Parkinsons disease (PD). The purpose of this study was to determine if selective nigrostriatal degeneration could be reproduced by systemic exposure of mice to the widely used herbicide paraquat. Repeated intraperitoneal paraquat injections killed dopaminergic neurons in the substantia nigra (SN) pars compacta, as assessed by stereological counting of tyrosine hydroxylase (TH)-immunoreactive and Nissl-stained neurons. This cell loss was dose- and age-dependent. Several lines of evidence indicated selective vulnerability of dopaminergic neurons to paraquat. The number of GABAergic cells was not decreased in the SN pars reticulata, and counting of Nissl-stained neurons in the hippocampus did not reveal any change in paraquat-treated mice. Degenerating cell bodies were observed by silver staining, but only in the SN pars compacta, and glial response was present in the ventral mesencephalon but not in the frontal cortex and cerebellum. No significant depletion of striatal dopamine followed paraquat administration. On the other hand, enhanced dopamine synthesis was suggested by an increase in TH activity. These findings unequivocally show that selective dopaminergic degeneration, one of the pathological hallmarks of PD, is also a characteristic of paraquat neurotoxicity. The apparent discrepancy between pathological (i.e., neurodegeneration) and neurochemical (i.e., lack of significant dopamine loss) effects represents another important feature of this paraquat model and is probably a reflection of compensatory mechanisms by which neurons that survive damage are capable of restoring neurotransmitter tissue levels.

Rotenone, Paraquat, and Parkinson’s Disease

Background Mitochondrial dysfunction and oxidative stress are pathophysiologic mechanisms implicated in experimental models and genetic forms of Parkinson’s disease (PD). Certain pesticides may affect these mechanisms, but no pesticide has been definitively associated with PD in humans. Objectives Our goal was to determine whether pesticides that cause mitochondrial dysfunction or oxidative stress are associated with PD or clinical features of parkinsonism in humans. Methods We assessed lifetime use of pesticides selected by mechanism in a case–control study nested in the Agricultural Health Study (AHS). PD was diagnosed by movement disorders specialists. Controls were a stratified random sample of all AHS participants frequency-matched to cases by age, sex, and state at approximately three controls: one case. Results In 110 PD cases and 358 controls, PD was associated with use of a group of pesticides that inhibit mitochondrial complex I [odds ratio (OR) = 1.7; 95% confidence interval (CI), 1.0–2.8] including rotenone (OR = 2.5; 95% CI, 1.3–4.7) and with use of a group of pesticides that cause oxidative stress (OR = 2.0; 95% CI, 1.2–3.6), including paraquat (OR = 2.5; 95% CI, 1.4–4.7). Conclusions PD was positively associated with two groups of pesticides defined by mechanisms implicated experimentally—those that impair mitochondrial function and those that increase oxidative stress—supporting a role for these mechanisms in PD pathophysiology.

Comparison of kindreds with parkinsonism and α‐synuclein genomic multiplications

Genomic triplication of the α‐synuclein gene recently has been associated with familial Parkinsons disease in the Spellman–Muenter kindred. Here, we present an independent family, of Swedish‐American descent, with hereditary early‐onset parkinsonism with dementia due to α‐synuclein triplication. Brain tissue available from affected individuals in both kindreds provided the opportunity to compare their clinical, pathological, and biochemical phenotypes. Of note, studies of brain mRNA and soluble protein levels demonstrate a doubling of α‐synuclein expression, consistent with molecular genetic data. Pathologically, cornu ammonis 2/3 hippocampal neuronal loss appears to be a defining feature of this form of inherited parkinsonism. The profound implications of α‐synuclein overexpression for idiopathic synucleinopathies are discussed.

Lewy bodies and parkinsonism in families with parkin mutations

Previous work has established that compound mutations and homozygous loss of function of the parkin gene cause early‐onset, autosomal recessive parkinsonism. Classically, this disease has been associated with loss of dopaminergic neurons in the substantia nigra pars compacta and locus ceruleus, without Lewy body pathology. We have sequenced the parkin gene of 38 patients with early‐onset Parkinsons disease (<41 years). Two probands with mutations were followed up. Clinical evaluation of their families was performed, blinded to both genetic and pathological findings. Chromosome 6q25.2‐27 haplotype analysis was carried out independently of the trait; parkin gene expression was examined at both the RNA and protein levels. Haplotype analysis of these families revealed a common chromosome 6, with a novel 40 bp exon 3 deletion that cosegregated with disease. In the proband of the smaller kindred, an exon 7 R275W substitution was identified in addition to the exon 3 deletion; RNA analysis demonstrated that the mutations were on alternate transcripts. However, Lewy body pathology typical of idiopathic Parkinsons disease was found at autopsy in the proband from the smaller kindred. These data suggest that compound heterozygous parkin mutations and loss of parkin protein may lead to early‐onset parkinsonism with Lewy body pathology, while a hemizygous mutation may confer increased susceptibility to typical Parkinsons disease.

AETIOLOGY OF PARKINSON'S DISEASE

It is suggested here that in most cases of Parkinsons disease the cause may be an environmental factor, possibly toxic, superimposed on a background of slow, sustained neuronal loss due to advancing age.

The Parkinson's Complex: Parkinsonism Is Just the Tip of the Iceberg

A 78-year-old man presented with a 15-year history of chronic constipation. At age 68, he experienced a nearcomplete loss of his sense of smell. Recently, he has developed an unusual sleep disorder, characterized by abrupt and at times combative behavior during the night that has resulted in injury to his spouse on two separate occasions; he is referred to a sleep disorders clinic. For most physicians, this medical history would not immediately bring Parkinson’s disease (PD) to mind. Yet, accumulating clinical and pathological evidence suggests it should. The traditional “textbook” description of PD defines the disease as a progressive disorder characterized by the triad of rigidity, bradykinesia, and rest tremor. A large body of evidence suggests that these features are due to degeneration of the dopaminergic nigrostriatal system. Although these clinical features typically lead a patient to the door of the neurologist, it is now increasingly clear that parkinsonism is only one aspect of a multifaceted and complex disorder. Furthermore, it is increasing clear that at least some of these nonparkinsonian features can precede the onset of parkinsonism by years and perhaps even decades. This essay argues that parkinsonism represents the disease as seen through the somewhat myopic lens of the neurologist, whereas in reality, parkinsonism only represents the tip of the iceberg that makes up this diverse disease (Fig 1). If one accepts this view, then the time has come to radically rethink the complex of features that constitute the disorder, which might be better viewed as a “centrosympathomyenteric neuronopathy.” The implications of this thesis are of more than academic importance. A failure to reevaluate how we view this disease at a time when our knowledge about its clinical and pathological features is expanding rapidly will adversely affect not only efforts to improve the diagnosis and management of the patients that we care for, but also is likely to impede research into the cause of the disease and attempts to slow or halt its progression.

1-Methyl-4-phenylpyridinium ion (MPP+): Identification of a metabolite of MPTP, a toxin selective to the substantia nigra

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a newly described neurotoxin which selectively destroys cells in the substantia nigra when administered systemically to primates. Because the substance creates a condition in humans which is virtually indistinguishable from Parkinsons disease, interest has focused on its mechanism of action. We now report that MPTP appears to be rapidly metabolized after systemic administration in toxic amounts, and identify 1-methyl-4-phenylpyridinium ion (MPP+) as a probable major metabolite.

Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease.

Although the causes of Parkinsons disease (PD) are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and online survey instruments, we conducted the largest case-control genome-wide association study (GWAS) of PD based on a single collection of individuals to date (3,426 cases and 29,624 controls). We discovered two novel, genome-wide significant associations with PD–rs6812193 near SCARB2 (, ) and rs11868035 near SREBF1/RAI1 (, )—both replicated in an independent cohort. We also replicated 20 previously discovered genetic associations (including LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region), providing support for our novel study design. Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0.27. Finally, using sparse regression techniques, we constructed predictive models that account for 6%–7% of the total variance in liability and that suggest the presence of true associations just beyond genome-wide significance, as confirmed through both internal and external cross-validation. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinsons disease remains to be discovered.

Parkin Localizes to the Lewy Bodies of Parkinson Disease and Dementia with Lewy Bodies

Mutations in alpha-synuclein (alpha S) and parkin cause heritable forms of Parkinson disease (PD). We hypothesized that neuronal parkin, a known E3 ubiquitin ligase, facilitates the formation of Lewy bodies (LBs), a pathological hallmark of PD. Here, we report that affinity-purified parkin antibodies labeled classical LBs in substantia nigra sections from four related human disorders: sporadic PD, inherited alphaS-linked PD, dementia with LBs (DLB), and LB-positive, parkin-linked PD. Anti-parkin antibodies also detected LBs in entorhinal and cingulate cortices from DLB brain and alphaS inclusions in sympathetic gangliocytes from sporadic PD. Double labeling with confocal microscopy of DLB midbrain sections revealed that approximately 90% of anti-alpha S-reactive LBs were also detected by a parkin antibody to amino acids 342 to 353. Accordingly, parkin proteins, including the 53-kd mature isoform, were present in affinity-isolated LBs from DLB cortex. Fluorescence resonance energy transfer and immunoelectron microscopy showed that alphaS and parkin co-localized within brainstem and cortical LBs. Biochemically, parkin appeared most enriched in cytosolic and postsynaptic fractions of adult rat brain, but also in purified, alpha S-rich presynaptic elements that additionally contained parkins E2-binding partner, UbcH7. We conclude that parkin and UbcH7 are present with alphaS in subcellular compartments of normal brain and that parkin frequently co-localizes with alpha S aggregates in the characteristic LB inclusions of PD and DLB. These results suggest that functional parkin proteins may be required during LB formation.