Multiple system atrophy: diagnostic methods and biomarkers

Multiple system atrophy (MSA) is a neurodegenerative disease belonging to a group of synucleinopathies and characterized by significant autonomic failure, parkinsonian syndrome, and cerebellar signs. Diagnostic criteria used currently were updated in 2022. While the clinical method and neuroimaging are typically diagnostic in MSA, new modalities are currently emerging. Novel candidate biomarkers are being intensively and thoroughly studied. The review analyzes the clinical picture and diagnostic criteria of the disease, describes imaging methods for diagnosing synucleinopathies, as well as known laboratory markers of multiple system atrophy

Identification of RNA markers associated with Parkinson's disease using multiplex gene expression analysis

Introduction. Parkinson's disease (PD) is a neurodegenerative disorder, and the development of biomarkers is essential due to complicated PD diagnosis and progression assessment. Objective. To identify PD RNA markers by multiplex expression profiling of 760 genes associated with the main neuropathological processes. Materials and methods. We studied the expression of 760 genes associated with the main neuropathological processes using Nanostring nCounter Human Neuropathology Panel in 29 blood samples obtained from PD patients, including 13 samples from those in the early stage and 16 samples from those in the advanced stage, and in 16 control blood samples. Results. The comparison of gene expression in the patients with early PD and in the controls demonstrated differential expression of genes CDKN1A and CPT1B. The comparison of gene expression in the patients with advanced PD and in the controls showed LRP1 upregulation in the advanced PD group. We also revealed СPT1B upregulation in advanced disease, with a positive correlation between СPT1B expression and PD duration. Discussion. The variably expressed genes may be relevant as PD biomarkers for diagnosis and progression assessment

A First-in-Class β-Glucuronidase Responsive Conjugate for Selective Dual Targeted and Photodynamic Therapy of Bladder Cancer

In this report, we present a novel prodrug strategy that can significantly improve the efficiency and selectivity of combined therapy for bladder cancer. Our approach involved the synthesis of a conjugate based on a chlorin-e6 photosensitizer and a derivative of the tyrosine kinase inhibitor cabozantinib, linked by a β-glucuronidase-responsive linker. Upon activation by β-glucuronidase, which is overproduced in various tumors and localized in lysosomes, this conjugate released both therapeutic modules within targeted cells. This activation was accompanied by the recovery of its fluorescence and the generation of reactive oxygen species. Investigation of photodynamic and dark toxicity in vitro revealed that the novel conjugate had an excellent safety profile and was able to inhibit tumor cells proliferation at submicromolar concentrations. Additionally, combined therapy effects were also observed in 3D models of tumor growth, demonstrating synergistic suppression through the activation of both photodynamic and targeted therapy

Whole-Exome Sequencing in Searching for New Variants Associated With the Development of Parkinson’s Disease

Background: Parkinson’s disease (PD) is a complex disease with its monogenic forms accounting for less than 10% of all cases. Whole-exome sequencing (WES) technology has been used successfully to find mutations in large families. However, because of the late onset of the disease, only small families and unrelated patients are usually available. WES conducted in such cases yields in a large number of candidate variants. There are currently a number of imperfect software tools that allow the pathogenicity of variants to be evaluated.Objectives: We analyzed 48 unrelated patients with an alleged autosomal dominant familial form of PD using WES and developed a strategy for selecting potential pathogenetically significant variants using almost all available bioinformatics resources for the analysis of exonic areas.Methods: DNA sequencing of 48 patients with excluded frequent mutations was performed using an Illumina HiSeq 2500 platform. The possible pathogenetic significance of identified variants and their involvement in the pathogenesis of PD was assessed using SNP and Variation Suite (SVS), Combined Annotation Dependent Depletion (CADD) and Rare Exome Variant Ensemble Learner (REVEL) software. Functional evaluation was performed using the Pathway Studio database.Results: A significant reduction in the search range from 7082 to 25 variants in 23 genes associated with PD or neuronal function was achieved. Eight (FXN, MFN2, MYOC, NPC1, PSEN1, RET, SCN3A and SPG7) were the most significant.Conclusions: The multistep approach developed made it possible to conduct an effective search for potential pathogenetically significant variants, presumably involved in the pathogenesis of PD. The data obtained need to be further verified experimentally

Data_Sheet_1_Whole-Exome Sequencing in Searching for New Variants Associated With the Development of Parkinson’s Disease.DOCX

<p>Background: Parkinson’s disease (PD) is a complex disease with its monogenic forms accounting for less than 10% of all cases. Whole-exome sequencing (WES) technology has been used successfully to find mutations in large families. However, because of the late onset of the disease, only small families and unrelated patients are usually available. WES conducted in such cases yields in a large number of candidate variants. There are currently a number of imperfect software tools that allow the pathogenicity of variants to be evaluated.</p><p>Objectives: We analyzed 48 unrelated patients with an alleged autosomal dominant familial form of PD using WES and developed a strategy for selecting potential pathogenetically significant variants using almost all available bioinformatics resources for the analysis of exonic areas.</p><p>Methods: DNA sequencing of 48 patients with excluded frequent mutations was performed using an Illumina HiSeq 2500 platform. The possible pathogenetic significance of identified variants and their involvement in the pathogenesis of PD was assessed using SNP and Variation Suite (SVS), Combined Annotation Dependent Depletion (CADD) and Rare Exome Variant Ensemble Learner (REVEL) software. Functional evaluation was performed using the Pathway Studio database.</p><p>Results: A significant reduction in the search range from 7082 to 25 variants in 23 genes associated with PD or neuronal function was achieved. Eight (FXN, MFN2, MYOC, NPC1, PSEN1, RET, SCN3A and SPG7) were the most significant.</p><p>Conclusions: The multistep approach developed made it possible to conduct an effective search for potential pathogenetically significant variants, presumably involved in the pathogenesis of PD. The data obtained need to be further verified experimentally.</p

Data_Sheet_2_Whole-Exome Sequencing in Searching for New Variants Associated With the Development of Parkinson’s Disease.docx

<p>Background: Parkinson’s disease (PD) is a complex disease with its monogenic forms accounting for less than 10% of all cases. Whole-exome sequencing (WES) technology has been used successfully to find mutations in large families. However, because of the late onset of the disease, only small families and unrelated patients are usually available. WES conducted in such cases yields in a large number of candidate variants. There are currently a number of imperfect software tools that allow the pathogenicity of variants to be evaluated.</p><p>Objectives: We analyzed 48 unrelated patients with an alleged autosomal dominant familial form of PD using WES and developed a strategy for selecting potential pathogenetically significant variants using almost all available bioinformatics resources for the analysis of exonic areas.</p><p>Methods: DNA sequencing of 48 patients with excluded frequent mutations was performed using an Illumina HiSeq 2500 platform. The possible pathogenetic significance of identified variants and their involvement in the pathogenesis of PD was assessed using SNP and Variation Suite (SVS), Combined Annotation Dependent Depletion (CADD) and Rare Exome Variant Ensemble Learner (REVEL) software. Functional evaluation was performed using the Pathway Studio database.</p><p>Results: A significant reduction in the search range from 7082 to 25 variants in 23 genes associated with PD or neuronal function was achieved. Eight (FXN, MFN2, MYOC, NPC1, PSEN1, RET, SCN3A and SPG7) were the most significant.</p><p>Conclusions: The multistep approach developed made it possible to conduct an effective search for potential pathogenetically significant variants, presumably involved in the pathogenesis of PD. The data obtained need to be further verified experimentally.</p