P. A. Slominsky

MOLECULAR MECHANISMS OF PATHOGENESIS OF PARKINSON'S DISEASE

Parkinsons disease is a complex disease characterized by a progressive degeneration of nigrostriatal dopaminergic neurons. The development of this condition is defined by the interaction between the genetic constitution of an organism and environmental factors. Analysis of the genes associated with development of monogenic forms of disease has allowed pointing out several mechanisms involved in Parkinsons disease pathogenesis such as the ubiquitin-proteasome degradation, differentiation of dopaminergic neurons, mitochondrial dysfunction, oxidative damage, and others. In this review, a variety of data which throw light on molecular mechanisms underlying pathogenesis of Parkinsons disease will be considered.

Spinocerebellar ataxia type 1 in Russia

Spinocerebellar ataxia type 1 (SCA1) is one form of autosomal dominant cerebellar ataxia (ADCA) caused by trinucleotide (CAG) repeat expansion within a mutant gene. We investigated 25 patients from 15 Russian ADCA families for SCA1 mutation and found an expanded CAG repeat in 5 families. Mutant chromosomes contained 41–51 CAG repeats (mean 46.1, SD 3.1), and normal chromosomes displayed 21–27 repeat units (mean 24.7, SD 1.3). Progressive cerebellar ataxia in our series of SCA1 patients was very commonly associated with dysarthria (in all cases) and pyramidal signs (in 10 of 11 cases). In three patients from one family we found optic atrophy, which has never been described before in genetically proven cases of SCA1. We observed no specific clinical features distinguishing SCA1 from non-SCA1 patients. In contrast to the high frequency of SCA1 in our series, we found no patients with Machado-Joseph disease, another form of ADCA caused by expanded CAG repeat.

Sporadic ALS associated with the D90A Cu,Zn superoxide dismutase mutation in Russia.

Twenty blood samples from Russian patients (Moscow) with idiopathic motor neurone disease were analysed for mutations in the Cu,Zn superoxide dismutase (Cu,Zn SOD) gene. Two patients (10%) with the amyotrophic lateral sclerosis (ALS) form of the disease were found to have a disease‐related mutation. One patient appears to have autosomal recessive adult‐onset ALS associated with homozygosity for D90A and presents the characteristic phenotype of very slowly ascending paresis with both lower and upper motor neurone signs. Another patient, heterozygous for D90A, presents ALS with lumbar onset and rapid progression. This is the first report of a Cu,Zn SOD mutation in ALS in Russia.

Mutation analysis of the parkin gene in Russian families with autosomal recessive juvenile parkinsonism

Autosomal recessive juvenile parkinsonism (AR‐JP) is a form of hereditary parkinsonism characterized by variable clinical presentations and caused by mutations in a novel gene, parkin, on chromosome 6q25.2–27. Until now, no Russian cases of parkin‐associated AR‐JP have been reported on. We recruited 16 patients from 11 Russian families with dopa‐responsive movement disorders according to the following criteria: 1) family history compatible with autosomal recessive inheritance; 2) onset of symptoms at ≤30 years of age; and 3) the lack of mutations in the GTP cyclohydrolase I gene (in sporadic cases). Mutation screening of the parkin gene was carried out by a semiquantitative PCR assay and direct sequencing of the coding region. Six different parkin mutations (both deletions and point mutations) were identified in the index cases from four families, including a novel point mutation in the donor splice site (IVS1+1G→A). The majority of our parkin‐associated cases were characterized by early‐onset dopa‐responsive parkinsonism with benign course and slow progression (5 patients from two families have been followed for as long as 18–36 years), and 1 patient had a phenotype of dopa‐responsive dystonia. This first description of Russian patients with AR‐JP and molecularly proven parkin mutations confirms the widespread occurrence of this polymorphic hereditary extrapyramidal disorder.

MicroRNAs: Possible role in pathogenesis of Parkinson’s disease

Parkinson’s disease is one of the most common human neurodegenerative disorders caused by the loss of dopaminergic neurons from the substantia nigra pars compacta of human brain. However, causes and mechanisms of the progression of the disease are not yet fully clarified. To date, investigation of the role of miRNAs in norm and pathology is one of the most intriguing and actively developing areas in molecular biology. MiRNAs regulate expression of a variety of genes and can be implicated in pathogenesis of various diseases. Possible role of miRNAs in pathogenesis of Parkinson’s disease is discussed in this review.

A common leucine-rich repeat kinase 2 gene mutation in familial and sporadic Parkinson's disease in Russia

A PARK8 form of Parkinsons disease (PD) is caused by a novel gene, leucine‐rich repeat kinase 2 (LRRK2), and a single mutation G2019S was found in a proportion of LRRK2‐associated cases of diverse ethnic origins. We performed the LRRK2 G2019S mutation analysis in 304 Russian patients with PD, including 291 sporadic and 13 autosomal dominant cases. The frequency of the LRRK2 G2019S was 0.7% amongst the sporadic patients (2/291) and 7.7% amongst familial PD (1/13). The mutation was also found in three unaffected relatives and absent in 700 control chromosomes. One patient carrying the LRRK2 G2019S was found earlier to have an additional mutation, a heterozygous duplication of exon 5 of the parkin gene. All patients carrying the LRRK2 G2019S exhibited typical levodopa‐responsive parkinsonism, and severe levodopa‐induced dyskinesia was observed in the patient carrying the LRRK2 and parkin mutations. There was notable variability in ages of the disease onset in G2019S carriers not explained by APOE genotypes. Two subsets of G2019S‐positive patients had different PARK8 haplotypes suggesting that the LRRK2 G2019S in Russian patients had arisen independently on different chromosomes. Identification of common LRRK2 mutations in some PD patients without an overt family history has notable implications for genetic counseling.

ITPR1 gene p.Val1553Met mutation in Russian family with mild Spinocerebellar ataxia

BackgroundSpinocerebellar ataxias (SСAs) are a highly heterogeneous group of inherited neurological disorders. The symptoms of ataxia vary in individual patients and even within the same SCA subtype. A study of a four-generation family with autosomal dominant (AD) non-progressive SCA with mild symptoms was conducted. The genotyping of this family revealed no frequent pathogenic mutations. So the objective of this study was to identify the genetic causes of the disease in this family with the technology of whole-exome sequencing (WES).Methods and resultsWES, candidate variant analysis with further Sanger sequencing, mRNA secondary structure prediction, and RSCU analysis were performed; a heterozygous missense mutation in ITPR1 was identified.ConclusionOur study confirms the fact that ITPR1 gene plays a certain role in the pathogenesis of SCAs, and, therefore, we suggest that c.4657G>A p.Val1553Met) is a disease-causing mutation in the family studied.

Polymorphism of STR Loci of the Y Chromosome in Three Populations of Eastern Slavs from Belarus, Russia, and Ukraine

Allelic polymorphism of five microsatellite loci of the human Y chromosome (DYS19, DYS390, DYS391, DYS392, and DYS393) was analyzed in samples of male populations from Ukraine, Russia, and Belarus (152 subjects in total). The allelic diversity indices (Dg) were determined for all loci; they varied from 0.23 to 0.72. The mean values of this parameter in the Ukrainian, Russian, and Belarussian populations were 0.45, 0.47, and 0.52, respectively. A total of 53 different haplotypes were found in 152 subjects from three populations. The most frequent haplotype was found in 14.5% of the subjects, whereas 35 haplotypes (23%) were each found in only one person. The haplotypic diversity index (Dhp) was 0.94. The genetic distances between the populations studied and some populations of Western and Central Europe were estimated. These data were used to construct a phylogram (tree) of genetic similarity between the populations, which demonstrated that the three Eastern Slavic populations are genetically close to one another and remote from Western European populations.

Mitochondrial dysfunction and oxidative damage in the molecular pathology of Parkinson’s disease

Parkinson’s disease is a complex disorder that is characterized by progressive degeneration of nigrostriatal dopaminergic neurons. Its development is determined by the interaction between the genetic constitution of a body and environmental factors. Analysis of the genes associated with monogenic forms of Parkinson’s disease implicated proteasomal degradation, differentiation of dopaminergic neurons, mitochondrial dysfunction, and oxidative damage in its pathogenesis. The review considers ample data that suggest a key role for mitochondrial dysfunction and oxidative stress.

Polymorphism of trinucleotide repeats in loci DM, DRPLA and SCA1 in East European populations

A normal polymorphism at three triplet repeat loci (myotonic dystrophy (DM), dentatorubral-pallidoluysian atrophy (DRPLA) and spinocerebellar ataxia type 1 (SCA1)) were examined in healthy unrelated individuals from the Siberian Yakut (Mongoloid) population, the Adygei (Caucasian) population and nine East European populations: populations from Russia (Holmogory, Oshevensk, Kursk, Novgorod, Udmurts, Bashkir), two Ukrainian populations (Lviv and Alchevsk) and one Belarussian. The distribution of alleles for DRPLA and SCA1 were similar for all East-European populations. For the DM locus, East European populations had typical allele distribution profiles with two modes, (CTG)5 and (CTG)11–14, but some differences were found for the Bashkir population where alleles containing 11–14 CTG repeats had relatively higher frequency. The Yakut population had different allele spectra for all types of repeats studied. Higher heterozygosity levels and insignificant differences between expected and observed heterozygosity were found for all tested loci. The latter led us to suggest that the trinucleotide repeat loci analysed are not influenced by selection factors and could be useful for genetic relationship investigations in different populations.