The Role of Presynaptic Cytomatrix Protein Bassoon (BSN) in Tau Pathology and Propagation

Neurodegenerative disorders have become a global health threat following a prolonged lifespan, with the majority involving the accumulation and propagation of pathological tau. Tau oligomers can migrate to presynaptic terminals and interact with surrounding proteins, among which Bassoon (BSN) is one that selectively binds to and colocalises with misfolded tau. Studies have reported numerous implications of BSN mutations in tau pathology, including promoting tau seeding activity, hyperphosphorylation, misfolding, and aggregation. These eventually lead to the formation of neurofibrillary tangles in tauopathies. Given the BSN's physiological role in maintaining synapses, its mutation also impairs synaptic integrity. These abnormalities are consistently attenuated by downregulating BSN levels. However, BSN downregulation can lead to tau hyperphosphorylation via an alternative pathway, CDK5 hyperactivity. Current findings hypothesize that BSN reduces tau clearance by inhibiting proteasome activity. It is also suggested that BSN can impair dopaminergic pathways prior to the detection of tau pathological features. Tunnelling nanotubes also emerge as a potential interneuronal route for BSN-mediated tau spread. Despite a lack of clinical evidence, findings from postmortem samples, in vitro, and preclinical models highlight BSN as a potential candidate for tau-targeting therapies, indicating its role in the pathological development of tau. The involvement of BSN in tau seeding might also resolve challenges posed by tau-targeting drugs during clinical trials. Hence, this article aims to provide new insights into recent findings on BSN and tau with reference to previous studies. We will discuss the possible mechanisms involved, along with the future therapeutic value of BSN in the treatment of tauopathies.