Alpha-synuclein and microtubule-associated protein tau aggregates (aSyn/Tau aggregates)

Aggregated alpha-synuclein and tau protein represent the primary pathological hallmarks of several neurodegenerative diseases, often referred to as synucleinopathies and tauopathies, respectively. Alpha-synuclein (encoded by the SNCA gene) is a presynaptic protein that misfolds into insoluble fibrils to form Lewy bodies, a defining feature of Parkinson's disease and dementia with Lewy bodies (UniProt P37840). Tau (encoded by the MAPT gene) is a microtubule-associated protein that, when hyperphosphorylated, aggregates into neurofibrillary tangles, which are central to the pathogenesis of Alzheimer's disease and frontotemporal dementia (UniProt P10636). While historically studied as separate entities, clinical and pathological evidence increasingly highlights their co-occurrence, where one aggregate may promote the templated misfolding of the other, leading to accelerated neurodegeneration (PMID: 31515468). Drug development targeting these aggregates focuses on immunotherapy to neutralize extracellular seeds and small molecules to inhibit intracellular aggregation or promote degradation (PubMed: 33053320). Effective targeting requires high selectivity for the pathological aggregate over the physiologically active monomer to minimize safety concerns and ensure therapeutic efficacy.

Other names

Lewy bodies and neurofibrillary tanglesSNCA and MAPT aggregatesPathological protein inclusionsCo-pathological protein aggregates

Therapeutic mechanisms include the use of monoclonal antibodies for passive immunization to sequester extracellular proteopathic seeds, active vaccines to induce endogenous antibody production, and small molecules designed to stabilize monomeric forms or inhibit the nucleation and elongation of amyloid-like fibrils (PubMed: 33053320).