Ann Clin Anesth Res | Volume 7, Issue 1 | Research Article | Open Access

Clonal Hematopoiesis as the Fundamental Mechanism to Launch Molecular-Biological Events Leading to Neurodegenerative Diseases of the Humans and as a Promising Target for their Therapy

Bryukhovetskiy AS^1*, Sharma HS² and Zhukova M¹

¹AO NeuroVita Clinical Hospital, Moscow, Russia
²Department of Surgical Sciences and Anesthesiology & Intensive Care Medicine, Uppsala University Hospital,
Russia

^*Correspondance to: Andrey S Bryukhovetskiy 

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Abstract

The goal of this work is to detect clonal hematopoiesis in the onset of Neurodegenerative Diseases (NDD) of the humans and to test the hypothesis that the NDDs are initiated and supported by the genomic damage and pathology-specific clones of Hematopoietic Stem Cells (HSCs). The trial included 20 cases of various NDDs including Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis (ALS) and others. The DNA was isolated from the HSCs of bone marrow and lymphocytes of the peripheral blood and tested by the method of New Generation Sequencing (NGS). Targeted paired-end exome sequencing of 22,000 genes was conducted to search for genetic polymorphisms specific to NDD and to identify Additional Somatic Mutations (ASMs) in clonality genes and stemness genes. Germ cell polymorphism, indicating a hereditary genesis of the disease, was detected in only one patient with NDD; all other diseases had a sporadic genesis. In all cases of progressing NDD, various mutations of clonality genes were identified, which indicates Clonal Hematopoiesis (CH). 123 ASMs were identified, of which 114 mutations were nucleotide substitutions of clonality genes and 9 mutations of stemness genes. If the total number of ASMs clonality genes is taken as 100%, then in patients with NDD, 18 types of mutations of the AKT1 gene clonality gene (16.5%), 16 types of mutations of the ASXL1 gene (14.67%), 20 types of mutations of the CBL gene (18.3%), 17 types of JAK2 gene mutations (15.6%), 12 types of PTEN gene mutations (11%), 1 type of PPM1D gene mutation (0.9%), 10 types of TET2 gene mutations (9.2%), 12 types of TP53 gene mutations (11%), 2 types of DNMT3A gene mutations (1.8%), 3 types of DNMT3b gene mutations (2.75%) and 1 type of DNMT1 gene mutation (0.9%). The mutations of stemness genes were few: 6 types of mutations of the NANOG gene and 3 types of mutations of the MTOR gene. It has been shown that ASMs in NDD are structurally different from ASMs in aging, suggesting a molecular genetic difference between these age-related disorders. Clonal hematopoiesis, identified in all patients with NDD, explains the constant activity of blood ICCs, which support systemic neuroinflammation in the “clinical axis of neurodegeneration” in NDD. Blocking clonal hematopoiesis may be a new strategy for treating and stopping the progression of NDD.

Keywords:

Neurodegenerative diseases; Alzheimer's disease; Parkinson's disease; Amyotrophic lateral sclerosis; Clonal hematopoiesis; Germ cell and somatic mutations; Hematopoietic stem sell

Citation:

Bryukhovetskiy AS, Sharma HS, Zhukova M. Clonal Hematopoiesis as the Fundamental Mechanism to Launch Molecular-Biological Events Leading to Neurodegenerative Diseases of the Humans and as a Promising Target for their Therapy. Ann Clin Anesth Res. 2023; 7(1): 1050..