HSP90-incorporating chaperome networks as biosensor for disease-related pathways in patient-specific midbrain dopamine neurons

Environmental and genetic risk factors contribute to Parkinson's Disease (PD) pathogenesis and the associated midbrain dopamine (mDA) neuron loss. Here, we identify early PD pathogenic events by developing methodology that utilizes recent innovations in human pluripotent stem cells (hPSC) and chemical sensors of HSP90-incorporating chaperome networks. We show that events triggered by PD-related genetic or toxic stimuli alter the neuronal proteome, thereby altering the stress-specific chaperome networks, which produce changes detected by chemical sensors. Through this method we identify STAT3 and NF-κB signaling activation as examples of genetic stress, and phospho-tyrosine hydroxylase (TH) activation as an example of toxic stress-induced pathways in PD neurons. Importantly, pharmacological inhibition of the stress chaperome network reversed abnormal phospho-STAT3 signaling and phospho-TH-related dopamine levels and rescued PD neuron viability. The use of chemical sensors of chaperome networks on hPSC-derived lineages may present a general strategy to identify molecular events associated with neurodegenerative diseases.publishe

Parkin and PINK1 Patient iPSC-Derived Midbrain Dopamine Neurons Exhibit Mitochondrial Dysfunction and α-Synuclein Accumulation

Parkinson's disease (PD) is characterized by the selective loss of dopamine neurons in the substantia nigra; however, the mechanism of neurodegeneration in PD remains unclear. A subset of familial PD is linked to mutations in PARK2 and PINK1, which lead to dysfunctional mitochondria-related proteins Parkin and PINK1, suggesting that pathways implicated in these monogenic forms could play a more general role in PD. We demonstrate that the identification of disease-related phenotypes in PD-patient-specific induced pluripotent stem cell (iPSC)-derived midbrain dopamine (mDA) neurons depends on the type of differentiation protocol utilized. In a floor-plate-based but not a neural-rosette-based directed differentiation strategy, iPSC-derived mDA neurons recapitulate PD phenotypes, including pathogenic protein accumulation, cell-type-specific vulnerability, mitochondrial dysfunction, and abnormal neurotransmitter homeostasis. We propose that these form a pathogenic loop that contributes to disease. Our study illustrates the promise of iPSC technology for examining PD pathogenesis and identifying therapeutic targets

Adipositas, Kognition und Entscheidungsverhalten

Entscheidungen zu fällen, ist ein integraler Bestandteil des täglichen Lebens. Im Kontext von Adipositas sind Entscheidungen von besonderem Interesse, die das Essverhalten und die physische Aktivität beeinflussen. Wie wir uns letztendlich entscheiden, hängt von einer Fülle von Faktoren ab. Diese sind unter anderem der erwartete Belohnungswert, der Aufwand, den es aufzubringen gilt, ob wir alle Alternativen kennen und schon Erfahrungen damit gesammelt haben, aber auch welche ausdrücklichen Ziele wir uns gesteckt haben. Zusätzlich bestimmt unser Gehirn, wie wahrscheinlich es ist, dass wir uns für die eine oder andere Alternative entscheiden. Warum aber fällt es Menschen mit Adipositas so schwer, ihr Verhalten so zu steuern, dass es mit ihren ausdrücklich formulierten Zielen übereinstimmt? Könnte es sein, dass Gehirnsysteme, welche die Entscheidungsfindung stützen, als Folge von Adipositas verändert sind? In diesem Kapitel sollen die Eigenheiten von Kognition, Entscheidungsfindung und Gehirnfunktion bei Adipositas hervorgehoben werden, die auf tiefgreifende Unterschiede zwischen Personen mit und ohne Adipositas in Gehirnsystemen hinweisen, die die Verhaltenskontrolle steuern. Unterschiede in diesen Hirnsystemen könnten eine mechanistische Erklärung dafür liefern, dass Personen mit Adipositas Schwierigkeiten gegenüber stehen, wenn sie versuchen, ihr Verhalten zu ändern

A global synthesis reveals biodiversity-mediated benefits for crop production.

Human land use threatens global biodiversity and compromises multiple ecosystem functions critical to food production. Whether crop yield-related ecosystem services can be maintained by a few dominant species or rely on high richness remains unclear. Using a global database from 89 studies (with 1475 locations), we partition the relative importance of species richness, abundance, and dominance for pollination; biological pest control; and final yields in the context of ongoing land-use change. Pollinator and enemy richness directly supported ecosystem services in addition to and independent of abundance and dominance. Up to 50% of the negative effects of landscape simplification on ecosystem services was due to richness losses of service-providing organisms, with negative consequences for crop yields. Maintaining the biodiversity of ecosystem service providers is therefore vital to sustain the flow of key agroecosystem benefits to society