Whole-Transcriptome Analysis of Mouse Models with MPTP-Induced Early Stages of Parkinson's Disease Reveals Stage-Specific Response of Transcriptome and a Possible Role of Myelin-Linked Genes in Neurodegeneration.

Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons. A whole-transcriptome analysis of the substantia nigra and striatum of an MPTP-induced mouse models of the earliest stages of PD was performed. Functional clustering of differentially represented transcripts revealed processes associated with the functioning of synapses, dendrites, axons, and myelination of neuronal projections. All of these processes occur in both the substantia nigra and striatum, but they are aimed at the functioning of neuron terminals in the striatum. One cluster was identified at the earliest stage modeled, i.e., "neuron projection" in the substantia nigra and "transport" in the striatum, and their number increased at subsequent stages. The number of clusters in the striatum predominates over those in the substantia nigra and there is a pronounced increase in the number of clusters from the modeled early stages to the late stages. These findings indicate that the substantia nigra and striatum have unique patterns of changes at each stage. Considering the clustering of individual processes, it was seen that there is a set of hierarchical clusters that overlap only partially at different stages and in different tissues. The data indicate a consistent involvement of the transcriptome in the pathogenesis of PD and highlight the independent role of various brain structures and individual parts of nerve cells in the formation of a response to the development of neurodegeneration. Decreased myelination of neuronal projections may be associated with the development of PD in the models considered.

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

BACKGROUND: Spinocerebellar 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 RESULTS: WES, candidate variant analysis with further Sanger sequencing, mRNA secondary structure prediction, and RSCU analysis were performed; a heterozygous missense mutation in ITPR1 was identified. CONCLUSION: Our 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.

[Analysis of mutations in patients with suspected autosomal dominant form of the Parkinson disease].

The Parkinson disease (PD) is a severe neurological disorder. Diverse genetic systems and environmental factors are involved in the pathogenesis of this disease. However, despite extensive research into the disease, its causes are not fully elucidated, and the exact spectrum of genes and mutations involved in the development of hereditary forms of PD has not been fully clarified yet. The present work is devoted to the analysis of mutations that lead to the development of monogenic forms of PD in patients with suspected autosomal dominant form of PD using Multiplex Ligation-dependent Probe Amplification (MLPA). We have identified several mutations (G2019S in LRRK2, heterozygous deletions of 2-3, 3-4 exons and heterozygous duplication of 2-4 exons in PARK2, deletion of 3 exon in PARK7) that lead to the development of PD in only 7 people out of 70 (18.4%), which suggests the need for further search of new mutations, for example, using exome sequencing. In the future it will help to develop the molecular genetic tests for early preclinical diagnosis and risk evaluation of the development of PD, and to understand better the causes and mechanisms of this disease.