Neurodegeneration and neuroprotection in Parkinson disease

Abstract

Many of the motoric features that define Parkinson disease (PD) result primarily from the loss of the neuromelanin (NM)-containing dopamine (DA) neurons of the substantia nigra (SN), and to a lesser extent, other mostly catecholaminergic neurons, and are associated with cytoplasmic "Lewy body" inclusions in some of the surviving neurons. While there are uncommon instances of familial PD, and rare instances of known genetic causes, the etiology of the vast majority of PD cases remains unknown (i.e., idiopathic). Here we outline genetic and environmental findings related to PD epidemiology, suggestions that aberrant protein degradation may play a role in disease pathogenesis, and pathogenetic mechanisms including oxidative stress due to DA oxidation that could underlie the selectivity of neurodegeneration. We then outline potential approaches to neuroprotection for PD that are derived from current notions on disease pathogenesis.

FIG. 1.

Age-specific prevalence rates of PD in different countries. This figure is a modification of a figure in de Rijk et al., provided by W. A. Rocca (personal communication, 2003), along with permission to reproduce.

FIG. 2.

Age- and sex-specific incidence of Parkinson disease. Data from Rochester, MN from 1975 to 1990. From Bower et al. with permission from the Movement Disorder Society.

FIG. 3.

MPTP (IV) is a byproduct sometimes formed in the illicit synthesis of MPPP (III), a narcotic that differs by a single methyl group from alphaprodine (1,3-dimethyl-4-phenyl-4-propionoxypiperidine; Nisentil). Compound I (3,6-dimethyl-6-phenyltetrahydro-1,3-oxazine), which can be produced from easily available ingredients, is treated with sulfuric or hydrochloric acid to produce II (1-methyl-4-phenyl-4- propionoxypiperidine; also called HPMP in Davis et al.21). Compound II, when treated with propionic anhydride and sulfuric acid is converted to III (1-methyl-4-phenyl-4-propionoxypiperidine; MPPP; PPMP in Davis et al.21). Under excess acidity, in the presence of “wet” propionic anhydride, or in the presence of dehydrating reagents, II can be converted to IV, (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine; MPTP; HPMP in Davis et al.21). Compound I can also be directly converted to MPTP in excess acid. Following entry into cells, monoamine oxidase (particularly MAO B, which is more highly expressed in astrocytes than DA neurons) in mitochondria converts MPTP (via conversion to 1-methyl-4-phenyl-2,3, dihydropyridinium; MPFP+, not shown) to V, MPP+ (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridinium), which is accumulated by catecholamine uptake transporters selectively into DA and other catecholamine neurons.

FIG. 4.

Histopathology of Lewy bodies (LB), from Duyckaerts. A: LB (arrow) in a pigmented neuron, showing dense central core and peripheral halo of the LB when stained with hematoxylin and eosin stain; the arrowhead points to neuromelanin within the cell. B: Immunostaining for ubiquitin reveals the presence of this protein within the central core of the LB. C: Immunostaining for alpha-synuclein reveals the presence of this protein within the surrounding halo of the LB. From Duyckaerts C. Les corps et prolongements de Lewy. Rev Neurol (Paris) 156:800–801. Copyright©Masson, Paris, 2000. All rights reserved.

FIG. 5.

Kaplan-Meier curves of the cumulative probability of reaching the endpoint (need for dopaminergic therapy) in the DATATOP study. Subjects receiving selegiline (deprenyl) averaged about 9 months longer before requiring dopaminergic therapy compared to placebo and alpha-tocopherol (which had the same outcome as placebo). From The Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 328:176–183, 1993. Copyright © 1993, Massachusetts Medical Society. All rights reserved.

FIG. 6.

Change in total UPDRS with different dosages of coenzyme Q₁₀. From Shults et al., Effects of Coenzyme Q₁₀ in early Parkinson disease-evidence slowing the functional decline. Arch Neurol 59:1541–1550. Copyrighted © 2002, American Medical Association. All rights reserved.

FIG. 7.

Change in the different components of the UPDRS with coenzyme Q_10.. From Shults et al., Effects of coenzyme Q₁₀ in early Parkinson disease-evidence of slowing of the functional decline. Arch Neurol 59:1541–1550. Copyrighted © 2002, American Medical Association. All rights reserved.