Tau-352 (0N3R) and Alpha Synuclein Co-Polymer Fibrils

Brain-specific tau isoforms vary in the number of N-terminal inserts and C- terminal repeat domains due to alternative splicing of exons; only the shortest isoform of tau, 0N3R, is expressed in the fetal brain during neurogenesis (1). Tau and alpha-synuclein polymerize into amyloid fibrils to form filamentous inclusions in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Tau has been shown to interact with alpha-synuclein in vitro (2), with synergistic cross-seeding between tau and alpha-synuclein resulting in polymerization of each other into fibrillary amyloid lesions in neuronal cultures and in vivo (3,4). Recombinant tau and alpha-synuclein co-polymer fibrils have demonstrated a more widespread transmission of induced pathology in a rodent model of tauopathies compared to pure Tau or alpha-synuclein fibrils alone (5). These co-polymer fibrils have also shown enhanced alpha-synuclein aggregation in vitro, and more severe alpha-synuclein pathology and Parkinson’s disease-like symptoms in mice (6).

MAPT, Fetal Tau, 0N3R, neurofibrillary tangle protein, paired-helical filament, PHFs, SNCA, NACP, PARK1, asyn, alpha-synuclein, pre-formed fibril, PFFs, mixed fibrils

Tau: MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL Asyn: MDVFMKGLSKAKEGVVAAAEKTKQGVAEAAGKTKEGVLYVGSKTKEGVVHGVATVAEKTKEQVTNVGGAVVTGVTAVAQKTVEGAGSIAAATGFVKKDQLGKNEEGAPQEGILEDMPVDPDNEAYEMPSEEGYQDYEPEA

1. Goedert et al. Multiple Isoforms of Human Microtubule-associated Protein Tau: Sequences and Localization in Neurofibrilary Tangles of Alzheimer’s Disease. Neuron. 1989;3(4):519-526. 2. Jensen et al. α-synuclein Binds to Tau and Stimulates the Protein Kinase A-catalyzed Tau Phosphorylation of Serine Residues 262 and 356. 1999. JBC. 274(36): 25481-25489. DOI:https://doi.org/10.1074/jbc.274.36.25481 3. Giasson et al. Initiation and Synergistic Fibrillization of Tau and Alpha-Synuclein. Science. 2003; 300: 636-40. DOI: 10.1126/science.1082324 4. Guo et al. Distinct α-synuclein Strains Differentially Promote Tau Inclusions in Neurons. 2013. Cell. 154(1) doi:10.1016/j.cell.2013.05.057. 5. Williams et al. Differential Cross-seeding Properties of Tau and α-synuclein in Mouse Models of Tauopathy and Synucleinopathy. Brain Communications. 2020; 2(2):fcaa090. doi:10.1093/braincomms/fcaa090 6. Pan et al. Tau Accelerates α-synuclein Aggregation and Spreading in Parkinson’s Disease. 2022. Brain. Doi: 10.1093/braiwac174