Promiscuous functions of the prion protein gene family

Editorial

10 February 2015

Promiscuous functions of the prion protein family

Sophie Mouillet-Richard

and

Jean-Luc Vilotte

7,515 views

4 citations

Editors

Sophie Mouillet-Richard

Institut National de la Santé et de la Recherche Médicale (INSERM)

Jean-Luc Vilotte

INRAE Centre Jouy-en-Josas

Impact

Review

11 February 2015

Biochemical insight into the prion protein family

Danica Ciric

and

Human Rezaei

Prion protein family comprises proteins, which share not only similarity in their primary structure, but also similarity in their fold. These two groups of similarity presume a parceling in their respective biological function through the common biochemical properties. In this review, biochemical and structural similarities of PrP and two other proteins, Doppel and Shadoo, are evocated. Some evidence demonstrating respectively similarity between PrP N-terminal and C-terminal domain with respectively Shadoo and Doppel is presented. We extended primary structure similarity analysis to the other PrP subdomain as 166-176 polyNQ domain and compare it to proteins using aggregation as a support for structural information transference and structural epigenetic. Finally, we questioned if prion protein family have conserved the PrP structural bistability, which should be at the origin of Prion phenomenon and if Prion pathology is not, ultimately, an exaptation of the physiological propensity of PrP to undergo a structural switch and polymerize.

8,732 views

21 citations

PrPC signaling via SFKs. Known physiological roles of PrPC such as neurotransmission, embryonic cell adhesion, olfactory function, and myelination converge at the use of SFKs as intracellular signaling partners. In this model, engagement of PrPC in various cis- or trans-interactions (depicted as “pathway activation”) elicits the catalytic activity of SFKs, leading to the modulation of diverse downstream targets that include ion channels, adhesion complexes, and cytosolic signaling molecules. Phosphorylation of transmembrane SFK targets controls their cell surface expression and/or signaling properties, whereas phosphorylation of intracellular SFK targets regulates the activation of additional downstream pathways, gene transcription, and protein translation. The caption below provides concrete examples of documented components of this cascade.

Perspective

28 October 2014

Common themes in PrP signaling: the Src remains the same

Katharina Ochs

and

Edward Málaga-Trillo

6,435 views

11 citations

Review

13 October 2014

To develop with or without the prion protein

Sophie Halliez

, 6 more and

Vincent Béringue

7,883 views

19 citations

$PrPC Dimerization activates a neuroprotective signaling pathway and the production of neuroprotective PrPC-derived metabolites. En route to the plasma membrane, a fraction of PrPC undergoes a physiological cleavage termed α-cleavage. Intracellular PrPC dimerization stimulates trafficking to the plasma membrane and the release of PrPN1 and PrPC1 at the cell surface. PrPC dimerization at the cell surface activates an intracellular signaling pathway with a neuroprotective outcome. At the cell surface, a fraction of PrPC undergoes ADAM10-mediated shedding. Double arrows indicate dimerization; dotted arrow indicates shedding. See text for details.$

Mini Review

09 October 2014

Regulation of PrPC signaling and processing by dimerization

Xavier Roucou

6,066 views

17 citations

Schematic representation of mammalian gonad differentiation. The genetic sex directs the development of the bipotential gonad toward a male or female gonadal fate. Three cellular types are present in differentiating gonad: somatic supporting cells, somatic steroid-producing cells, and germinal cells. Male and female somatic supporting cells have a common origin and differentiate respectively in Sertoli and granulosa cells. Steroidogenic cells will differentiate in Leydig cells in testis and theca cells in ovary. Testicular-specific features include the formation of the coelomic arterial vessel and of the seminiferous tubules formed by germ and Sertoli cells. Ovarian-specific features are in a chronological order: (i) entry of germ cells into meiosis, (ii) establishment of cortical and medullar compartments, and (iii) formation of follicles, which contain oocytes surrounded by granulosa cells. In agreement with the genetic sex, the development of the phenotypic sex is achieved with the differentiation of the genital tract: epididymis, vas deferens, seminal vesicle, prostate, and penis in males; oviduct, uterus and vagina in female (Adapted from DeFalco and Capel, 2009; for review).

Review

02 October 2014

Role of the prion protein family in the gonads

Aurélie Allais-Bonnet

and

Eric Pailhoux

10,567 views

20 citations

Mini Review

29 September 2014

PrPC from stem cells to cancer

Séverine Martin-Lannerée

, 5 more and

Sophie Mouillet-Richard

The cellular prion protein PrP^C was initially discovered as the normal counterpart of the pathological scrapie prion protein PrP^Sc, the main component of the infectious agent of Transmissible Spongiform Encephalopathies. While clues as to the physiological function of this ubiquitous protein were greatly anticipated from the development of knockout animals, PrP-null mice turned out to be viable and to develop without major phenotypic abnormalities. Notwithstanding, the discovery that hematopoietic stem cells from PrP-null mice have impaired long-term repopulating potential has set the stage for investigating into the role of PrP^C in stem cell biology. A wealth of data have now exemplified that PrP^C is expressed in distinct types of stem cells and regulates their self-renewal as well as their differentiation potential. A role for PrP^C in the fate restriction of embryonic stem cells has further been proposed. Paralleling these observations, an overexpression of PrP^C has been documented in various types of tumors. In line with the contribution of PrP^C to stemness and to the proliferation of cancer cells, PrP^C was recently found to be enriched in subpopulations of tumor-initiating cells. In the present review, we summarize the current knowledge of the role played by PrP^C in stem cell biology and discuss how the subversion of its function may contribute to cancer progression.

8,285 views

44 citations

Review

29 August 2014

Prion protein and aging

Lisa Gasperini

and

Giuseppe Legname

The cellular prion protein (PrP^C) has been widely investigated ever since its conformational isoform, the prion (or PrP^Sc), was identified as the etiological agent of prion disorders. The high homology shared by the PrP^C-encoding gene among mammals, its high turnover rate and expression in every tissue strongly suggest that PrP^C may possess key physiological functions. Therefore, defining PrP^C roles, properties and fate in the physiology of mammalian cells would be fundamental to understand its pathological involvement in prion diseases. Since the incidence of these neurodegenerative disorders is enhanced in aging, understanding PrP^C functions in this life phase may be of crucial importance. Indeed, a large body of evidence suggests that PrP^C plays a neuroprotective and antioxidant role. Moreover, it has been suggested that PrP^C is involved in Alzheimer disease, another neurodegenerative pathology that develops predominantly in the aging population. In prion diseases, PrP^C function is likely lost upon protein aggregation occurring in the course of the disease. Additionally, the aging process may alter PrP^C biochemical properties, thus influencing its propensity to convert into PrP^Sc. Both phenomena may contribute to the disease development and progression. In Alzheimer disease, PrP^C has a controversial role because its presence seems to mediate β-amyloid toxicity, while its down-regulation correlates with neuronal death. The role of PrP^C in aging has been investigated from different perspectives, often leading to contrasting results. The putative protein functions in aging have been studied in relation to memory, behavior and myelin maintenance. In aging mice, PrP^C changes in subcellular localization and post-translational modifications have been explored in an attempt to relate them to different protein roles and propensity to convert into PrP^Sc. Here we provide an overview of the most relevant studies attempting to delineate PrP^C functions and fate in aging.