Epigenetics in Lewy Body Diseases: Impact on Gene Expression, Utility as a Biomarker, and Possibilities for Therapy

Abstract

<jats:p>Lewy body disorders (LBD) include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). They are synucleinopathies with a heterogeneous clinical manifestation. As a cause of neuropathological overlap with other neurodegenerative diseases, the establishment of a correct clinical diagnosis is still challenging, and clinical management may be difficult. The combination of genetic variation and epigenetic changes comprising gene expression-modulating DNA methylation and histone alterations modifies the phenotype, disease course, and susceptibility to disease. In this review, we summarize the results achieved in the deciphering of the LBD epigenome. To provide an appropriate context, first LBD genetics is briefly outlined. Afterwards, a detailed review of epigenetic modifications identified for LBD in human cells, postmortem, and peripheral tissues is provided. We also focus on the difficulty of identifying epigenome-related biomarker candidates and discuss the results obtained so far. Additionally, epigenetic changes as therapeutic targets, as well as different epigenome-based treatments, are revised. The number of studies focusing on PD is relatively limited and practically inexistent for DLB. There is a lack of replication studies, and some results are even contradictory, probably due to differences in sample collection and analytical techniques. In summary, we show the current achievements and directions for future research.</jats:p>

Mitochondrial CHCHD2: Disease-Associated Mutations, Physiological Functions, and Current Animal Models

“…Pathologically, PD patients show gray matter loss in frontal brain regions while PDD patients show gray matter loss in temporal, occipital, and subcortical areas (Burton et al, 2004), although both diseases typically affect the brainstem (Kosaka, 2014). DLB is the third most common form of dementia after Alzheimer's Disease (AD) and vascular dementia (Jellinger, 2018;Urbizu and Beyer, 2020). DLB affects 1 to 2 percent of the population (Urbizu and Beyer, 2020), specifically having a higher incidence and prevalence in populations over 65 years old (Shiner et al, 2016).…”

“…DLB is the third most common form of dementia after Alzheimer's Disease (AD) and vascular dementia (Jellinger, 2018;Urbizu and Beyer, 2020). DLB affects 1 to 2 percent of the population (Urbizu and Beyer, 2020), specifically having a higher incidence and prevalence in populations over 65 years old (Shiner et al, 2016). It is primarily sporadic and shares genetic risk determinants with PD and AD (Selikhova et al, 2009).…”

“…Another distinguishing feature of DLB is a higher load of cortical Lewy body pathology in the temporal and parietal brain regions (Masliah, 2001;Selikhova et al, 2009). While DLB and PDD are synucleinopathies with similar incidence rates (Jellinger, 2018;Urbizu and Beyer, 2020), differences arise in the order of symptom onset. Patients with PDD develop motor symptoms first and then later show symptoms of dementia, while patients with DLB are diagnosed with dementia and then later show motor impairments (Burton et al, 2004;Kosaka, 2014).…”

Phytochemicals as Regulators of Genes Involved in Synucleinopathies

“…DLB is an age-associated neurodegenerative disease characterized by a progressive cognitive decline that restricts daily activities and affects everyday life. DLB develops due to a combination of genetic variations and epigenetic changes, including DNA methylation and histone alterations modulating the level of gene expression [ 24 ]. DLB is associated with the accumulation of misfolded α-synuclein in Lewy bodies and Lewy neurites [ 25 ] ( Figure 1 C).…”

Systematic Analysis of the Lysine Crotonylome and Multiple Posttranslational Modification Analysis (Acetylation, Succinylation, and Crotonylation) in Candida albicans

“…Compared with “classic” DNA epigenetics, PTM affects gene expression through amino acid residues such as lysine in histone. Recently, novel therapies based on targeting various epigenetic mechanisms have been applied under a variety of disease and immunological conditions such as autoimmunity ( 6 ), cancer ( 7 , 8 ), neurodegenerative disease ( 9 ), and immunological disorders ( 10 ). With specific regard to PTM, the protein can be modified by acetylation, phosphorylation, succinylation, crotonylation, methylation, butyrylation, propionylation, glutarylation, etc.…”