Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration

Abstract

Highlights d APEX-mapped Tau interactome at subcellular and amino acid levels in human neurons d Activity-dependent binding of Tau to synaptic vesicle proteins during Tau secretion d FTD mutations reduce Tau binding to mitochondria proteins and impair bioenergetics d Tau interactors modified by FTD mutation are downregulated in human tauopathy Authors

Ultrastructural and biochemical classification of pathogenic tau, α-synuclein and TDP-43

“…It will be important to clarify whether the disease-specific fold is established at the point of initial fibrillar species formation or at some other point during the maturation process, both in order to elucidate the mechanism of the strain formation and to characterize the pathological transition from pre-tangles/pre-inclusions to fibrillar inclusions. Recently, comprehensive proteomic analysis has identified a number of proteins that interact with tau, α-syn and TDP-43 [ 99 , 123 , 181 , 292 ]. A similar approach would be useful to identify cell type-specific proteins that interact with pathogenic proteins and are involved in strain formation.…”

Microglia phenotypes are associated with subregional patterns of concomitant tau, amyloid-β and α-synuclein pathologies in the hippocampus of patients with Alzheimer’s disease and dementia with Lewy bodies

“…In a previous study, the local co-distribution of NFTs and Lewy bodies was found more frequent in limbic areas than other brain parts [ 17 ]. Tau and synuclein proteins seem to be part of the same interactome in induced pluripotent stem cells (iPSC)-derived neuron models [ 89 ] but our observations contradict the idea of a stereotypic dual pathology in the AD and DLB hippocampus. How pSyn- and pTau-bearing neighbouring neurons co-inhabit the AD and DLB hippocampus and how the two pathologies coincide in few others remains to be understood.…”

Unbiased proteomic profiling reveals the IP3R modulator AHCYL1/IRBIT as a novel interactor of microtubule-associated protein tau

“…Our evidence implies that tau can interact with AHCYL1/IRBIT in cell-free assays as well as in cultured cells. Although we did not define the interacting domains of the two molecules, we speculate that they may be within the region highly conserved between AHCYL1/IRBIT and SAH hydrolase (AHCY), given that recent data indicate that tau can also interact with AHCY in iPSC-derived glutamatergic neurons ( 41 ).…”

“…Among them, DNAJ/heat shock protein 40 kD, S100 calcium-binding protein B, and bridging integrator 1 were previously described as bona fide tau interactors ( 37 , 38 , 39 , 40 ), highlighting the quality of our in vitro proteomic analysis. Two additional polypeptides, Src substrate cortactin and MAP RP/EB family member 2, were also retrieved in a recently reported tau interactome in induced pluripotent stem cell (iPSC)–derived glutamatergic neurons ( 41 ). We focused our study on AHCYL1/IRBIT, a protein that modulates IP3R activity ( 42 , 43 , 44 ) and therefore with a potential role in mitochondrial bioenergetics that may be relevant in tauopathies as recently emphasized ( 41 ).…”

“…Two additional polypeptides, Src substrate cortactin and MAP RP/EB family member 2, were also retrieved in a recently reported tau interactome in induced pluripotent stem cell (iPSC)–derived glutamatergic neurons ( 41 ). We focused our study on AHCYL1/IRBIT, a protein that modulates IP3R activity ( 42 , 43 , 44 ) and therefore with a potential role in mitochondrial bioenergetics that may be relevant in tauopathies as recently emphasized ( 41 ). It is known that the C-terminal region of AHCYL1/IRBIT is highly homologous to the adenosylhomocysteinase AHCY, whereas the N-terminal region (residues 1–105) is unique for the IRBIT family members across phyla ( 44 , 45 ).…”