The genome can be attacked by endogenous and exogenous sources inducing DNA damage. To counteract threats posed by DNA lesions, eukaryotic cells have evolved mechanisms, collectively termed as DNA damage response (DDR), whose key players are the highly conserved protein kinases ATR and ATM. Recent studies highlight the role of DNA damage in the progression of neuronal loss in a broad spectrum of human neurodegenerative diseases (ND). Accumulation of DNA damage is a pervasive phenomenon in aged brains, including within telomeric repeats, and it is elevated in brains of patients suffering from ND. However, whetherthe increased level of DNA damage in ND is a cause rather than the consequence of neurodegeneration remains to be established.
Protein aggregates constitute a neuropathological hallmark of ND, but their exact role in the pathogenesis of these diseases is still debated. Recent studies from Unit 1 demonstrated that ATM responds to mechanical stimuli when cells experience mechanical stretching, and it promotes recovery after mechanically-induced cytoskeletal stress. These cytoskeletal alterations, which are common to several ND, may be facilitated by formation of intracellular protein aggregates, which are typically associated with ND pathogenesis and are plausible sources of endogenous mechanical forces. alpha-synuclein (alpha-Syn) and Tau are proteins involved in aggregation in ND, including Parkinson’s (PD) and Alzheimer’s disease (AD). Interestingly, although alpha-Syn and Tau are considered cytosolic, they are expressed in the nucleus, bind DNA and RNA, and interact with histones and DDR components, suggesting that they can cause DNA damage and/or impair DNA repair. Furthermore, preliminary data from Unit 3 show that alpha-Syn localizes to sites of transcription stress and that nuclear alpha-Syn is highly mobile, and its mobility is reduced in fibroblasts from PD patients, which also display reduced DNA repair capacity. These findings suggest that DNA damage and transcription stress in neurons can cause reduction in alpha-Syn mobility, which then functions as aggregation seed. Interestingly, Unit 4 recently demonstrated RNA-dependent phase separation events of DDR factors at DNA lesions.
On these premises, we aim at determining (i) the role of ATM and ATR in mechanically induced cytoskeletal alterations in neurons; (2) the role of protein aggregation as source of detrimental endogenous mechanical forces in neurons; (3) the role of DNA damage and transcription stress in the formation of aggregates; and (4) the roles of alpha-Syn and Tau proteins in DNA repair, as well as the contribution of DNA lesions towards alpha-Syn- and Tau-mediated toxicity. The information provided by this project could offer completely novel insights into the pathogenesis of these intractable, devastating diseases, therefore paving the road for new therapeutic strategies.