The complexity of tau in Alzheimer's disease.

Accumulation of misfolded and aggregated forms of tau protein in the brain is a neuropathological hallmark of tauopathies, such as Alzheimer's disease and frontotemporal lobar degeneration. Tau aggregates have the ability to transfer from one cell to another and to induce templated misfolding and aggregation of healthy tau molecules in previously healthy cells, thereby propagating tau pathology across different brain areas in a prion-like manner. The molecular mechanisms involved in cell-to-cell transfer of tau aggregates are diverse, not mutually exclusive and only partially understood. Intracellular accumulation of misfolded tau induces several mechanisms that aim to reduce the cellular burden of aggregated proteins and also promote secretion of tau aggregates. However, tau may also be released from cells physiologically unrelated to protein aggregation. Tau secretion involves multiple vesicular and non-vesicle-mediated pathways, including secretion directly through the plasma membrane. Consequently, extracellular tau can be found in various forms, both as a free protein and in vesicles, such as exosomes and ectosomes. Once in the extracellular space, tau aggregates can be internalized by neighboring cells, both neurons and glial cells, via endocytic, pinocytic and phagocytic mechanisms. Importantly, accumulating evidence suggests that prion-like propagation of misfolding protein pathology could provide a general mechanism for disease progression in tauopathies and other related neurodegenerative diseases. Here, we review the recent literature on cellular mechanisms involved in cell-to-cell transfer of tau, with a particular focus in tau secretion.

/pdf/mechanisms-of-secretion-and-spreading-of-pathological-tau-h9lyi7wjll.pdf

Mechanisms of secretion and spreading of pathological tau protein

Role of tau protein in Alzheimer's disease: The prime pathological player.

Most secretory proteins travel through a well-documented conventional secretion pathway involving the endoplasmic reticulum (ER) and the Golgi complex. However, recently, it has been shown that a significant number of proteins reach the plasma membrane or extracellular space via unconventional routes. Unconventional protein secretion (UPS) can be divided into two types: (i) the extracellular secretion of cytosolic proteins that do not bear a signal peptide (i.e. leaderless proteins) and (ii) the cell-surface trafficking of signal-peptide-containing transmembrane proteins via a route that bypasses the Golgi. Understanding the UPS pathways is not only important for elucidating the mechanisms of intracellular trafficking pathways but also has important ramifications for human health, because many of the proteins that are unconventionally secreted by mammalian cells and microorganisms are associated with human diseases, ranging from common inflammatory diseases to the lethal genetic disease of cystic fibrosis. Therefore, it is timely and appropriate to summarize and analyze the mechanisms of UPS involvement in disease pathogenesis, as they may be of use for the development of new therapeutic approaches. In this Review, we discuss the intracellular trafficking pathways of UPS cargos, particularly those related to human diseases. We also outline the disease mechanisms and the therapeutic potentials of new strategies for treating UPS-associated diseases.

Unconventional protein secretion – new insights into the pathogenesis and therapeutic targets of human diseases

Transmission of α-synuclein seeds in neurodegenerative disease: recent developments

Cell-to-cell transmission of misfolded proteins propagates proteotoxic stress in multicellular organisms when transmitted polypeptides serve as a seeding template to cause protein misfolding in recipient cells, but how misfolded proteins are released from cells to initiate this process is unclear. Misfolding-associated protein secretion (MAPS) is an unconventional protein-disposing mechanism that specifically exports misfolded cytosolic proteins including various neurodegenerative disease-causing proteins. Here we establish the HSC70 co-chaperone DNAJC5 as an essential mediator of MAPS. USP19, a previously uncovered MAPS regulator binds HSC70 and acts upstream of HSC70 and DNAJC5. We further show that as a membrane-associated protein localized preferentially to late endosomes and lysosomes, DNAJC5 can chaperone MAPS client proteins to the cell exterior. Intriguingly, upon secretion, misfolded proteins can be taken up through endocytosis and eventually degraded in the lysosome. Collectively, these findings suggest a transcellular protein quality control regulatory pathway in which a deubiquitinase-chaperone axis forms a “triaging hub”, transferring aberrant polypeptides from stressed cells to healthy ones for disposal.

/pdf/dnajc5-facilitates-usp19-dependent-unconventional-secretion-2bxy6dgf6v.pdf

DNAJC5 facilitates USP19-dependent unconventional secretion of misfolded cytosolic proteins

Role of E2-RING Interactions in Governing RNF4-Mediated Substrate Ubiquitination.

The present invention describes that OTUB1 cleavage of K48 polyubiquitin is stimulated by a select subset of E2 enzymes, and that this stimulation is regulated by the ubiquitin-charged state of the E2 and free ubiquitin. Structural and biochemical studies of OTUB1 and UBCH5B show that the E2 stimulates binding of the polyubiquitin substrate by contacting the OTUB1 N-terminal ubiquitin-binding helix. Methods for identifying E2 enzymes which stimulate or inhibit OTUB1 cleavage of K48 polyubiquitin, as well as novel target compounds which modulate this interaction are provided.

Methods for identifying proteins and compounds that modulate the activity of otub1

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DNAJC5 facilitates USP19-dependent unconventional secretion of misfolded cytosolic proteins

Role of E2-RING Interactions in Governing RNF4-Mediated Substrate Ubiquitination.

Methods for identifying proteins and compounds that modulate the activity of otub1