Mitochondrial dysfunction in Parkinson's disease.

This review discusses the etiology and pathogenesis of Parkinson's disease (PD). Mitochondrial respiratory failure and oxidative stress appear to be two major contributors to nigral neuronal death in PD. Complex I deficiency has been reported by several groups and appears to be one of the basic abnormalities responsible for mitochondrial failure. The principal question is whether or not complex I deficiency is primary or secondary. The second question is whether or not complex I deficiency is localized in the nigrostriatal system or is systemically present. It is our impression that complex I deficiency is not the primary cause but that its deficiency appears to be systemic. The primary cause may be the combination of genetic background and potential nigral neurotoxins. Exposure of nigral neurons to a high risk for oxidative damage because of its high dopamine content may be the reason for more pronounced nigral complex I deficiency compared to systemic organs. Oxidative stress and mitochondrial failure produce a vicious cycle in nigral neurons. To explore the genetic risk factors of sporadic PD, studies on familial PD and parkinsonism are important. Recently, an autosomal dominant form of familial PD was found to be caused by point mutations of the alpha-synuclein gene, and an autosomal recessive familial parkinsonism was mapped to the long arm of chromosome 6 near the Mn-SOD gene locus. Information obtained in these familial cases will contribute to the research on sporadic PD.

Refinement of the gene locus for autosomal recessive juvenile parkinsonism (AR-JP) on chromosome 6q25.2-27 and identification of markers exhibiting linkage disequilibrium.

Autosomal recessive juvenile parkinsonism (AR-JP) (MIM 600116) is a hereditary neurodegenerative disorder characterized by levodopa-responsive parkinsonism with a mean age at onset of 23.2 years. We recently mapped the AR-JP gene locus to a 17-cM interval on chromosome 6q25.2-27. To further narrow the candidate region of the AR-JP gene, we performed detailed linkage analysis using densely placed genetic markers in this region (D6S437, D6S1581, D6S1579, D6S305, D6S411, SOD2, D6S253, D6S1599, D6S1719 and D6S264). Pairwise linkage analysis revealed the highest cumulative maximal lod score of 9.13 at D6S1579 (theta = 0.05), and multipoint linkage analysis revealed the highest cumulative lod score of 12.4 at the locus 3 cM telomeric to D6S1599. Observation of obligate recombination events narrowed the candidate region to a 13-cM region between D6S1579 and D6S264. Furthermore, we identified two marker loci, D6S1579 and D6S1599, which exhibit strong linkage disequilibrium with the AR-JP locus: chi 2 (2 x n table) = 84.22; P < 0.0001, chi 2 [likelihood-ratio test (LRT)] = 20.66; P < 0.0001, lambda = 0.40 and chi 2 (2 x n table) = 63.37; P < 0.0001, chi 2 (LRT) = 10.32; P < 0.0001, lambda = 0.30, respectively. These results suggest that the candidate region for the AR-JP gene is most likely located near the 4-cM region encompassing D6S1579 and D6S1599.

Mn SOD activity and protein in a patient with chromosome 6-linked autosomal recessive parkinsonism in comparison with Parkinson's disease and control.

We report Mn superoxide dismutase (SOD) protein and activity in a patient with familial autosomal recessive Lewy body-negative parkinsonism in comparison with patients with sporadic Parkinson's disease (PD) and controls. We recently proved linkage of this family with markers of chromosome 6 at 6q25.2-27, which included the Mn SOD gene. We used a novel polymorphic mutation at -9 position of the signal peptide of the Mn SOD precursor protein, which caused valine to alanine substitution. All the affected members of this family showed homozygosity for alanine, whereas nonaffected members, sporadic PD patients, and the control subjects studied showed either heterozygosity of alanine and valine or homozygosity of valine. The Mn SOD activity of this familial patient was the highest among the PD patients and the control subjects studied, and an abundant expression of Mn SOD was found in the substantia nigra. The molecular weight of Mn SOD protein by Western blotting of this patient was essentially similar to that of PD patients and the control subjects. High Mn SOD activity may constitute a genetic risk factor in this familial patient. The difference in the signal peptide sequence may affect the expression of Mn SOD within mitochondria; however, it is unlikely that loss of function type Mn SOD mutation is the cause of this familial parkinsonism. Mn SOD in sporadic PD patients was similar to that in controls.

Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2-27.

An autosomal recessive form of juvenile Parkinsonism (AR-JP) (MIM 600116) is a levodopa-responsive Parkinsonism whose pathological finding is a highly selective degeneration of dopaminergic neurons in the zona compacta of the substantia nigra. By linkage analysis of diallelic polymorphism of the Mn-superoxide dismutase gene (SOD2), we found a family with AR-JP showing perfect segregation of the disease with the SOD2 locus. By extending the linkage analysis to 13 families with AR-JP, we discovered strong evidence for the localization of the AR-JP gene at chromosome 6q25.2-27, including the SOD2 locus, with the maximal cumulative pairwise LOD scores of 7.26 and 7.71 at D6S305 (theta = .03) and D6S253 (theta = .02), respectively. Observation of obligate recombination events, as well as multipoint linkage analysis, placed the AR-JP gene in a 17-cM interval between D6S437 and D6S264. Delineation of the AR-JP gene will be an important step toward our understanding of the molecular mechanism underlying selective degeneration of the nigral neurons.

Structural dimorphism in the mitochondrial targeting sequence in the human manganese superoxide dismutase gene. A predictive evidence for conformational change to influence mitochondrial transport and a study of allelic association in Parkinson's disease.

Mitochondrial targeting sequence (MTS) has a common property to form an amphiphilic helical structure which is essential for its effective transport of mitochondrial protein. Natural polymorphism in human MTS which affects its mitochondrial transport ability has not been reported. Furthermore, no structural polymorphism for manganese superoxide dismutase (MnSOD) gene has been studied in human population. We here identify diallelic polymorphism (Ala-9Val) in the MTS of human MnSOD in a Japanese population. Calculation of a helix forming potential predicted the typical amphiphilic helical structure in -9Ala allele and its disruption in -9Val allele. We here suggest that this mutation may reflect functional polymorphism of mitochondrial transport of human MnSOD. An association study using this polymorphism showed significant allelic deviation for -9Ala allele (12.1% vs. 19.3%) in Parkinson's disease.

[The elevation of serum creatine kinase in the course of Parkinson disease.--in relation to malignant syndrome].

In the long course of Parkinson disease, we encounter the elevation of serum creatine kinase (CK) occasionally. Such elevation was not necessarily accompanied by severe symptoms as malignant syndrome. To delineate the basis of its situation, we selected the patients showing CK-elevation from 697 cases of Parkinson disease who had entered our hospital and their serum CK level had been measured. The cases with common cause of CK-elevation like trauma or myocardial infarction were excluded in advance. Those patients with CK-elevation were investigated with reference to age, gender, severity, duration of illness, dementia, and psychiatric symptoms retrospectively. High CK level was observed in 95 cases who were composed predominantly of advanced male patients. No obvious anticipatory cause of CK-elevation like a modification of anti-parkinson drug was recognized in 65 cases. On the other hand, CK-elevation caused by the modification of anti-parkinson drug was recognized in 10 cases. CK-elevation was observed in patients with dementia, delirium, and hallucination at higher rate. Most of these patients with CK-elevation did not show high fever and did not necessarily meet the criteria of malignant syndrome. However, 9 cases who showed marked increase of CK level over 10 times of upper limit of normal value contained some cases who had features of malignant syndrome. In Parkinson disease, especially in advanced cases dopamine may be unstable controlled in a few locations of their brain. Some situation of the disease may elicit imbalance of dopamine in patients' brain and induce CK elevation as in the similar condition in which neuroleptics are administrated.

MRI findings in the mild type of mucopolysaccharidosis II (Hunter's syndrome).

Neuroradiological findings in a 44-year-old male with the typical mild type of Hunter's disease are reported. Cranial MRI revealed patchy areas of increased and decreased signals in T1- and T2-weighted images in the thalamus and the basal ganglia giving rise to a honey comb-like appearance as a whole. The deep white matter showed high signals in the T2-weighted image. To our knowledge, the honey comb-like appearance has never been reported in this disorder. Deposition of mucopolysaccharides and/or glycolipids and increase in fluid content seem to be responsible for these changes.