Ageing and epigenetics: linking neurodevelopmental and neurodegenerative disorders

Abstract

Epigenetics has classically been recognized as crucial to neurodevelopment and neurodevelopmental disorders. More recently its role in ageing processes, including neurodegenerative disorders has emerged, although far more research is required in this area, particularly in humans. Epigenetic processes that regulate gene expression comprise strata of DNA modification (e.g. methylation), histone modification (e.g. histone acetylation), and mRNA translation (e.g. by microRNAs). These strata are progressively more fluid whereby changes in DNA methylation may persist for many years whilst expression of microRNAs fluctuates over short periods. There is considerable 'cross-talk' between these epigenetic strata. Epigenetic mechanisms are open to parental imprinting and thus they are candidates for linking diseases, not just over the life course, but also intergenerationally. There is a genetic overlap between intellectual disability and cognitive ageing. Epigenetic pathways may strengthen the links between neurodevelopmental disorders and neurodegenerative diseases.

Comparative Analysis of Multiple Neurodegenerative Diseases Based on Advanced Epigenetic Aging Brain

“…Enrichment analysis was then performed based on each of the shortest paths, the special functions (i.e., the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and the Biological Process (BP) term in Gene Ontology (GO), shown in Figure 5 and Table 5 ). These indicated multiple dysfunctions of different ND types ( McGeer et al, 1989 ; Behl, 2000 ; Nagatsu et al, 2000 ; Everse et al, 2011 ; Obulesu and Lakshmi, 2014 ; Caputi and Giron, 2018 ; Cui and Xu, 2018 ; Yan et al, 2018 ; Liu et al, 2019 ; Porro et al, 2019 ; Starr, 2019 ; Ashrafizadeh et al, 2020 ; Burgaletto et al, 2020 ; Luo et al, 2020 ; Paul et al, 2021 ), respectively.…”

SHANK2 mutations impair apoptosis, proliferation and neurite outgrowth during early neuronal differentiation in SH-SY5Y cells

“…Furthermore, it is expressed during early neuronal differentiation at sites where SHANK2 is also expressed [23][24][25]46 . In addition, there is increasing evidence showing that molecular and cellular processes involved in neurodevelopment are also relevant to the pathology of neurodegenerative diseases 47,48 . One connection could be the pathological reactivation during neurodegeneration of genetic programs physiologically relevant during neurodevelopment, especially in Alzheimer's disease 49 .…”

“…One connection could be the pathological reactivation during neurodegeneration of genetic programs physiologically relevant during neurodevelopment, especially in Alzheimer's disease 49 . There is also a genetic overlap between intellectual disability and cognitive aging 48 . Since SHANK2 is involved in fundamental molecular and cellular processes in neurons, it is plausible that its role might also be relevant in neurodegeneration.…”

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

“…A developmental origin for neurodegenerative disorders, including amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD), Huntington’s disease (HD), Parkinson’s disease (PD), Alzheimer’s disease (AD), and mild cognitive impairment (MCI), has been considered for many years ( Gardener et al, 2010 ; Kovacs et al, 2014 ; Arendt et al, 2017 ; Ruzo et al, 2018 ; Wiatr et al, 2018 ; Kiernan et al, 2019 ; Starr, 2019 ; Lulé et al, 2020 ; Wang Z. et al, 2020 ), and recent clinical, genomic and molecular studies have uncovered evidence linking neurodevelopmental changes and neurodegenerative diseases. The onset of amyotrophic lateral sclerosis (ALS) may be related to neonatal dysfunction due to imbalances in excitation and inhibition ( Kiernan et al, 2019 ), perhaps arising from the mutation of genes involved in neurodevelopment (i.e., C9orf72 ) ( Yeh et al, 2018 ).…”