Age-dependent neuroinflammation and cognitive decline in a novel Ala152Thr-Tau transgenic mouse model of PSP and AD.

Introduction: Mutations of Tau are associated with several neurodegenerative disorders. Recently, the Tau mutation A152T was described as a novel risk factor for frontotemporal dementia spectrum disorders and Alzheimer disease. In vitro Tau-A152T shows a decreased binding to microtubules and a reduced tendency to form abnormal fibers.

Preventive methylene blue treatment preserves cognition in mice expressing full-length pro-aggregant human Tau.

Introduction: Neurofibrillary tangles (NFT) composed of Tau are hallmarks of neurodegeneration in Alzheimer disease. Transgenic mice expressing full-length pro-aggregant human Tau (2N4R Tau-ΔK280, termed Tau(ΔK)) or its repeat domain (TauRD-ΔK280, TauRD(ΔK)) develop a progressive Tau pathology with missorting, phosphorylation, aggregation of Tau, loss of synapses and functional deficits. Whereas TauRD(ΔK) assembles into NFT concomitant with neuronal death, Tau(ΔK) accumulates into Tau pretangles without overt neuronal loss.

Emerging modes of PINK1 signaling: another task for MARK2.

PTEN-induced kinase 1 (PINK1) acts at multiple levels to promote mitochondrial health, including regulatory influence on ATP-synthesis, protein quality control, apoptosis, mitochondrial transport, and destiny. PINK1 mutations are linked to Parkinson disease (PD) and mostly result in loss of kinase activity. But the molecular events responsible for neuronal death as well as the physiological targets and regulators of PINK1 are still a matter of debate.

Microtubule affinity-regulating kinase 2 (MARK2) turns on phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) at Thr-313, a mutation site in Parkinson disease: effects on mitochondrial transport.

The kinase MARK2/Par-1 plays key roles in several cell processes, including neurodegeneration such as Alzheimer disease by phosphorylating tau and detaching it from microtubules. In search of interaction partners of MARK2, we identified phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1), which is important for the survival of neurons and whose mutations are linked to familial Parkinson disease (PD). MARK2 phosphorylated and activated the cleaved form of PINK1 (ΔN-PINK1; amino acids 156-581).

The tau of MARK: a polarized view of the cytoskeleton.

Microtubule-affinity regulating kinases (MARKs) were originally discovered by their ability to phosphorylate tau protein and related microtubule-associated proteins (MAPs), and thereby to regulate microtubule dynamics in neurons. Members of the MARK (also known as partition-defective [Par]-1 kinase) family were subsequently found to be highly conserved and to have key roles in cell processes such as determination of polarity, cell-cycle control, intracellular signal transduction, transport and cytoskeleton. This is important for neuronal differentiation, but is also prominent in neurodegenerative 'tauopathies' such as Alzheimer's disease.

Interactions of MAP/microtubule affinity regulating kinases with the adaptor complex AP-2 of clathrin-coated vesicles.

MARK [microtubule-associated proteins (MAPs)/microtubule affinity regulating kinase]/Par-1 (partition defective) phosphorylate MAPs tau, MAP2 and MAP4 at KXGS motifs and thereby regulate microtubule dynamics and transport processes in cells [Drewes et al., Cell1997;89:297-308]. We report here that MARK copurifies with clathrin-coated vesicles (CCVs) via interaction with the adaptor complex AP-2.

Spred1 and TESK1--two new interaction partners of the kinase MARKK/TAO1 that link the microtubule and actin cytoskeleton.

The signaling from MARKK/TAO1 to the MAP/microtubule affinity-regulating kinase MARK/Par1 to phosphorylated microtubule associated proteins (MAPs) renders microtubules dynamic and plays a role in neurite outgrowth or polarity development. Because hyperphosphorylation of Tau at MARK target sites is a hallmark of Alzheimer neurodegeneration, we searched for upstream regulators by the yeast two-hybrid approach and identified two new interaction partners of MARKK, the regulatory Sprouty-related protein with EVH-1 domain1 (Spred1) and the testis-specific protein kinase (TESK1). Spred1-MARKK binding has no effect on the activity of MARKK; therefore, it does not change microtubule (MT) stability.

PAK5 kinase is an inhibitor of MARK/Par-1, which leads to stable microtubules and dynamic actin.

MARK/Par-1 is a kinase involved in development of embryonic polarity. In neurons, MARK phosphorylates tau protein and causes its detachment from microtubules, the tracks of axonal transport. Because the target sites of MARK on tau occur at an early stage of Alzheimer neurodegeneration, we searched for interaction partners of MARK.