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Catalytic Cross Talk between Key Peptide Fragments That Couple Alzheimer’s Disease with Amyotrophic Lateral Sclerosis

Veronica Laos, Dezmond Bishop, Pritam Ganguly, Grace Schonfeld, Ellen Trapp, Kristi Lazar Cantrell, Steven K. Buratto, Joan-Emma Shea, Michael T. Bowers
Journal of the American Chemical Society 2021 v.143 no.9 pp. 3494-3502
amyotrophic lateral sclerosis, atomic force microscopy, brain, cognitive disorders, mass spectrometry, molecular dynamics, mutants, neurotoxicity, peptides
Protein aggregation is a common feature in prominent neurodegenerative diseases, usually thought to be due to the assembly of a single peptide or protein. Recent studies have challenged this notion and suggested several proteins may be involved in promoting and amplifying disease. For example, the TDP-43 protein associated with Amyotrophic Lateral Sclerosis has been found in the brain along with Aβ assemblies associated with Alzheimer’s disease, and those patients that show the presence of TDP-43 are 10 times more likely to demonstrate cognitive impairment compared to TDP-43-negative Alzheimer’s patients. Here we examine the interactions between the amyloidogenic core of TDP-43, TDP-43₃₀₇₋₃₁₉, and a neurotoxic physiologically observed fragment of Aβ, Aβ₂₅₋₃₅. Utilizing ion mobility mass spectrometry in concert with atomic force microscopy and molecular dynamics simulations, we investigate which oligomers are involved in seeding aggregation across these two different protein systems and gain insight into which structures initiate and result from these interactions. Studies were conducted by mixing Aβ₂₅₋₃₅ with the toxic wild type TDP-43₃₀₇₋₃₁₉ peptide and with the nontoxic synthetic TDP-43₃₀₇₋₃₁₉ mutant, G314V. Our findings identify a strong catalytic effect of TDP-43₃₀₇₋₃₁₉ WT monomer in the acceleration of Aβ₂₅₋₃₅ aggregation to its toxic cylindrin and β barrel forms. This observation is unprecedented in both its speed and specificity. Interestingly, the nontoxic G314V mutant of TDP-43₃₀₇₋₃₁₉ and dimers or higher order oligomers of WT TDP-43₃₀₇₋₃₁₉ do not promote aggregation of Aβ₂₅₋₃₅ but rather dissociate preformed toxic higher order oligomers of Aβ₂₅₋₃₅. Reasons for these very different behaviors are reported.