Interaction of tau with the neural plasma membrane mediated by tau's amino-terminal projection domain.

Abstract

Abstract. The neuronal microtubule-associated protein tau is required for the development of cell polarity in cultured neurons. Using PC12 cells that stably express tau and tau amino-terminal fragments, we report that tau interacts with the neural plasma membrane through its amino-terminal projection domain. In differentiated PC12 transfectants, tau is found in growth cone-like structures in a nonmicrotubule-dependent manner. In hippocampal neurons, tau is differentially extracted by detergent and enriched in the growth cone and the distal axon when membrane is left intact. In PC12 transfectants, overexpression of tau's amino-terminal fragment, but not of full-length tau, suppresses NGF-induced process formation. Our data suggest that tau's amino-terminal projection domain has an important role in neuritic development and establishes tau as a mediator of microtubule-plasma membrane interactions.

Role of N-terminal tau domain integrity on the survival of cerebellar granule neurons

“…In contrast, in our tau (1-230) construct R1 was absent and P2 was deleted from the last 12 aminoacids in which, for example, a functional SH3-binding domain is present. 46 On the other hand, our reports are in agreement with those of Brandt et al 5 , demonstrating that the overexpression of the N-terminal domain of the rat tau protein (1-203 and 1-233) is not harmful to PC12 cells.…”

“…51 It must pointed out that none of the sites cited above underwent hyperphosphorylation in CGNs overexpressing tau (1-230) or tau (1-441) (Figure 4d), suggesting that these peptides could affect the neuronal functions by interacting with some cytoplasmic membrane components. Whether such an action is exerted via competition with the internal pool of tau at the membrane level, as suggested by Brandt's finding 5 or via other mechanisms, remains to be elucidated.…”

“…In this connection, it has been reported that tau interacts with neuronal plasma membrane components through the amino-terminal projection domain, 5 and that this interaction is impaired by phosphorylation at sites that are altered in PHF, such as those recognized by mAb AT8, PHF-1, and PHF-6. 51 It must pointed out that none of the sites cited above underwent hyperphosphorylation in CGNs overexpressing tau (1-230) or tau (1-441) (Figure 4d), suggesting that these peptides could affect the neuronal functions by interacting with some cytoplasmic membrane components.…”

“…5 In order to quantify the amount of exogenous tau expression accurately, cellular homogenates were pretreated with alkaline phosphatase before application to the gel. In tau (1-441) and tau (1-230) cells infected with 30 MOI, the level of expression -monitored using mAb TAU-1 -was Btwo-fold higher, relative to the endogenous tau used as an internal standard for normalization (not shown).…”

“…It has been hypothesized that the Nterminal domain operates as a molecular transducer between cytoplasmic membrane components and MTs having an important role in neurite formation during differentiation of the PC12 cell line. 5 It likely plays a role in the phospholipase (PLC)-g signal transduction pathway, as suggested by the finding that tau coimmunoprecipitates with active PLC-g 6,7 and that seven putative binding sites for the SH3-binding domain of PLC-g are present in the N-terminal tau region. 8 Tau also binds directly or indirectly to phosphatidylinositol biphosphate (PIP 2 ) that serves as a precursor of diacyglicerol and inositol triphosphate, leading to the activation of PLCg, of PKC, and increase in cytosolic calcium.…”