DNA Methylation in Genetic and Sporadic Forms of Neurodegeneration: Lessons from Alzheimer's, Related Tauopathies and Genetic Tauopathies

Abstract

Genetic and sporadic forms of tauopathies, the most prevalent of which is Alzheimer's Disease, are a scourge of the aging society, and in the case of genetic forms, can also affect children and young adults. All tauopathies share ectopic expression, mislocalization, or aggregation of the microtubule associated protein TAU, encoded by the MAPT gene. As TAU is a neuronal protein widely expressed in the CNS, the overwhelming majority of tauopathies are neurological disorders. They are characterized by cognitive dysfunction often leading to dementia, and are frequently accompanied by movement abnormalities such as parkinsonism. Tauopathies can lead to severe neurological deficits and premature death. For some tauopathies there is a clear genetic cause and/or an epigenetic contribution. However, for several others the disease etiology is unclear, with few tauopathies being environmentally triggered. Here, we review current knowledge of tauopathies listing known genetic and important sporadic forms of these disease. Further, we discuss how DNA methylation as a major epigenetic mechanism emerges to be involved in the disease pathophysiology of Alzheimer's, and related genetic and non-genetic tauopathies. Finally, we debate the application of epigenetic signatures in peripheral blood samples as diagnostic tools and usages of epigenetic therapy strategies for these diseases.

Keywords: Alzheimer; DNA methylation; MAPT; TAU; epigenetics; neurodegeneration; neurogenetic disease; tauopathy.

Figure 1

Putative potential of CRISPR/dCas9 editing-based therapeutic approaches for tauopathies that display impaired methylation patterns of selected genes/key regulator elements. (a) In disease paradigms, impaired DNA methylation (e.g., hypomethylation of risk genes associated with Alzheimer’s Disease (AD) and related/other tauopathies) results in increased TAU expression, decreased TAU clearance, or mislocalization, all of which lead to the accumulation of TAU and eventually to the formation of TAU protein aggregates. Neurons affected by this TAU pathology become dysfunctional and decay, eventually leading to impaired cognitive function and neurodegeneration. (b) CRISPR/dCas9 editing approaches may restore methylation patterns of AD and tauopathy risk genes, preventing abnormal production or modification of TAU protein and NFT formation, preserving the physiological function of TAU (i.a. microtubule stabilization) and preventing or partially reverse brain damage and disease progression. Possible genetic and non-genetic interventions could be (i) drug-induced modulation of methylation patterns, (ii) gene-replacement or RNAi-based gene therapy, or (iii) site/gene-specific modulation of methylation, e.g., as depicted, site-specific methylation via dCas9-directed DNMT targeting. This figure produced by using BioRender.com with a respective publication licence, provided by the Biology department of the RWTH Aachen University.