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Neurodegenerative diseases (NDs), including the most prevalent Alzheimer's disease and Parkinson disease, share common pathological features. Despite decades of gene-centric approaches, the molecular mechanisms underlying these diseases remain widely elusive. In recent years, transposable elements (TEs), long considered 'junk' DNA, have gained growing interest as pathogenic players in NDs. Age is the major risk factor for most NDs, and several repressive mechanisms of TEs, such as heterochromatinization, fail with age. Indeed, heterochromatin relaxation leading to TE derepression has been reported in various models of neurodegeneration and NDs. There is also evidence that certain pathogenic proteins involved in NDs (e.g., tau, TDP-43) may control the expression of TEs. The deleterious consequences of TE activation are not well known but they could include DNA damage and genomic instability, altered host gene expression, and/or neuroinflammation, which are common hallmarks of neurodegeneration and aging. TEs might thus represent an overlooked pathogenic culprit for both brain aging and neurodegeneration. Certain pathological effects of TEs might be prevented by inhibiting their activity, pointing to TEs as novel targets for neuroprotection.

Heterochromatin disorganization is a key hallmark of aging and DNA methylation state is currently the main molecular predictor of chronological age. The most frequent neurodegenerative diseases like Parkinson disease and Alzheimer’s disease are age-related but how the aging process and chromatin alterations are linked to neurodegeneration is unknown. Here, we investigated the consequences of viral overexpression of Gadd45b, a multifactorial protein involved in active DNA demethylation, in the midbrain of wild-type mice. Gadd45b overexpression induces global and stable changes in DNA methylation, particularly on gene bodies of genes related to neuronal functions. DNA methylation changes were accompanied by perturbed H3K9me3-marked heterochromatin and increased DNA damage. Prolonged Gadd45b expression resulted in dopaminergic neuron degeneration accompanied by altered expression of candidate genes related to heterochromatin maintenance, DNA methylation or Parkinson disease. Gadd45b overexpression rendered midbrain dopaminergic neurons more vulnerable to acute oxidative stress. Heterochromatin disorganization and DNA demethylation resulted in derepression of mostly young LINE-1 transposable elements, a potential source of DNA damage, prior to Gadd45b-induced neurodegeneration. Our data implicate that alterations in DNA methylation and heterochromatin organization, LINE-1 derepression and DNA damage can represent important contributors in the pathogenic mechanisms of dopaminergic neuron degeneration with potential implications for Parkinson disease.