Endolysosomal pathway activity protects cells from neurotoxic TDP-43

The accumulation of protein aggregates in neurons is a typical pathological hallmark of the motor neuron disease amyotrophic lateral sclerosis (ALS) and of frontotemporal dementia (FTD). In many cases, these aggregates are composed of the 43 kDa TAR DNA-binding protein (TDP‑43). Using a yeast model for TDP‑43 proteinopathies, we observed that the vacuole (the yeast equivalent of lysosomes) markedly contributed to the degradation of TDP‑43. This clearance occurred via TDP‑43-containing vesicles fusing with the vacuole through the concerted action of the endosomal-vacuolar (or endolysosomal) pathway and autophagy. In line with its dominant role in the clearance of TDP‑43, endosomal-vacuolar pathway activity protected cells from the detrimental effects of TDP‑43. In contrast, enhanced autophagy contributed to TDP‑43 cytotoxicity, despite being involved in TDP‑43 degradation. TDP‑43’s interference with endosomal-vacuolar pathway activity may have two deleterious consequences. First, it interferes with its own degradation via this pathway, resulting in TDP‑43 accumulation. Second, it affects vacuolar proteolytic activity, which requires endosomal-vacuolar trafficking. We speculate that the latter contributes to aberrant autophagy. In sum, we propose that ameliorating endolysosomal pathway activity enhances cell survival in TDP‑43-associated diseases

Fließbandfertigung von Atmungskettenkomplexen in Mitochondrien

A key function of mitochondria consists of energy conversion, performed with the help of the respiratory chain and the ATP synthase. Biogenesis of these essential molecular machines requires expression of nuclear and mitochondrially encoded genes. We describe our current understanding how these processes are coordinated and how they are organized in specific areas of the inner membrane to facilitate the assembly of these sophisticated complexes

Welche Methoden braucht die Bildungsforschung? Eine fachdidaktische Perspektive

Die Frage, welche Forschungsmethoden eine bestimmte Disziplin bzw. ein bestimmtes Berufsfeld „braucht“ und demzufolge auch Gegenstand der Ausbildung sein müssen, ist sicher hochrelevant. Im Beitrag nehmen die Autoren, aus der Perspektive der Fachdidaktik (Physik), im Kern die Position ein, dass der Auswahl und Begründung von Methoden zwar eine zentrale Rolle im Forschungsprozess zukommt, gleichzeitig aber nicht im Vorhinein eine Festlegung auf bestimmte Methoden erfolgen kann, die das Forschungsfeld vermeintlich braucht bzw. nicht braucht. Sie leiten aus dieser Grundposition drei Thesen ab, die nach der Erläuterung von Vorannahmen den Beitrag strukturieren. Die Überlegungen basieren auf einem Statement von Claudia von Aufschnaiter in einer Podiumsdiskussion anlässlich eines Workshops zu Forschungsmethoden im November 2018 und greifen Diskussionsanregungen aus diesem Workshop auf. (DIPF/Orig.

Taking out the garbage: cathepsin D and calcineurin in neurodegeneration

Cellular homeostasis requires a tightly controlled balance between protein synthesis, folding and degradation. Especially long-lived, post-mitotic cells such as neurons depend on an efficient proteostasis system to maintain cellular health over decades. Thus, a functional decline of processes contributing to protein degradation such as autophagy and general lysosomal proteolytic capacity is connected to several age-associated neurodegenerative disorders, including Parkinson's, Alzheimer's and Huntington's diseases. These so called proteinopathies are characterized by the accumulation and misfolding of distinct proteins, subsequently driving cellular demise. We recently linked efficient lysosomal protein breakdown via the protease cathepsin D to the Ca2+/calmodulin-dependent phosphatase calcineurin. In a yeast model for Parkinson's disease, functional calcineurin was required for proper trafficking of cathepsin D to the lysosome and for recycling of its endosomal sorting receptor to allow further rounds of shuttling. Here, we discuss these findings in relation to present knowledge about the involvement of cathepsin D in proteinopathies in general and a possible connection between this protease, calcineurin signalling and endosomal sorting in particular. As dysregulation of Ca2+ homeostasis as well as lysosomal impairment is connected to a plethora of neurodegenerative disorders, this novel interplay might very well impact pathologies beyond Parkinson's disease

Employing a Force and Motion Learning Progression to Investigate the Relationship between Task Characteristics and Students’ Conceptions at Different Levels of Sophistication

Research has demonstrated that when learning mechanics, students’ conceptions (SCs) improve gradually (1) and are often activated depending on problem features (2). The aim of this study is to combine these two research lines to investigate how different task characteristics affect the activation of SCs at different levels of sophistication. Data were collected from N = 356 students using a paper–pencil test in which conceptual and contextual task characteristics (CCTCs) are varied systematically across ordered multiple-choice items. Answer options were constructed according to the four levels of a force and motion learning progression. Results, obtained using quantitative methods (e.g., Rasch analysis and regression), demonstrate that the effects of CCTCs may differ at different levels of SCs. For the direction of problem, for example, activating the correct conception, assuming force proportional to acceleration, seems to be easier in tasks asking for the resulting motion. However, activating more appropriate conceptions regarding lower levels, e.g., assuming force proportional to velocity, compared to a rather undifferentiated understanding of force and motion, seems to be easier in tasks asking for the forces. Results of our study can be used for choosing tasks with specific CCTCs to support conceptual change along specific steps of a learning path

Membrane-tethering of cytochrome c accelerates regulated cell death in yeast

Intrinsic apoptosis as a modality of regulated cell death is intimately linked to permeabilization of the outer mitochondrial membrane and subsequent release of the protein cytochrome c into the cytosol, where it can participate in caspase activation via apoptosome formation. Interestingly, cytochrome c release is an ancient feature of regulated cell death even in unicellular eukaryotes that do not contain an apoptosome. Therefore, it was speculated that cytochrome c release might have an additional, more fundamental role for cell death signalling, because its absence from mitochondria disrupts oxidative phosphorylation. Here, we permanently anchored cytochrome c with a transmembrane segment to the inner mitochondrial membrane of the yeast Saccharomyces cerevisiae, thereby inhibiting its release from mitochondria during regulated cell death. This cytochrome c retains respiratory growth and correct assembly of mitochondrial respiratory chain supercomplexes. However, membrane anchoring leads to a sensitisation to acetic acid-induced cell death and increased oxidative stress, a compensatory elevation of cellular oxygen-consumption in aged cells and a decreased chronological lifespan. We therefore conclude that loss of cytochrome c from mitochondria during regulated cell death and the subsequent disruption of oxidative phosphorylation is not required for efficient execution of cell death in yeast, and that mobility of cytochrome c within the mitochondrial intermembrane space confers a fitness advantage that overcomes a potential role in regulated cell death signalling in the absence of an apoptosome

Apitoxin and Its Components against Cancer, Neurodegeneration and Rheumatoid Arthritis : Limitations and Possibilities

Natural products represent important sources for the discovery and design of novel drugs. Bee venom and its isolated components have been intensively studied with respect to their potential to counteract or ameliorate diverse human diseases. Despite extensive research and significant advances in recent years, multifactorial diseases such as cancer, rheumatoid arthritis and neurodegenerative diseases remain major healthcare issues at present. Although pure bee venom, apitoxin, is mostly described to mediate anti-inflammatory, anti-arthritic and neuroprotective effects, its primary component melittin may represent an anticancer therapeutic. In this review, we approach the possibilities and limitations of apitoxin and its components in the treatment of these multifactorial diseases. We further discuss the observed unspecific cytotoxicity of melittin that strongly restricts its therapeutic use and review interesting possibilities of a beneficial use by selectively targeting melittin to cancer cells

Endolysosomal pathway activity protects cells from neurotoxic TDP-43

The accumulation of protein aggregates in neurons is a typical pathological hallmark of the motor neuron disease amyotrophic lateral sclerosis (ALS) and of frontotemporal dementia (FTD). In many cases, these aggregates are composed of the 43 kDa TAR DNA-binding protein (TDP‑43). Using a yeast model for TDP‑43 proteinopathies, we observed that the vacuole (the yeast equivalent of lysosomes) markedly contributed to the degradation of TDP‑43. This clearance occurred via TDP‑43-containing vesicles fusing with the vacuole through the concerted action of the endosomal-vacuolar (or endolysosomal) pathway and autophagy. In line with its dominant role in the clearance of TDP‑43, endosomal-vacuolar pathway activity protected cells from the detrimental effects of TDP‑43. In contrast, enhanced autophagy contributed to TDP‑43 cytotoxicity, despite being involved in TDP‑43 degradation. TDP‑43’s interference with endosomal-vacuolar pathway activity may have two deleterious consequences. First, it interferes with its own degradation via this pathway, resulting in TDP‑43 accumulation. Second, it affects vacuolar proteolytic activity, which requires endosomal-vacuolar trafficking. We speculate that the latter contributes to aberrant autophagy. In sum, we propose that ameliorating endolysosomal pathway activity enhances cell survival in TDP‑43-associated diseases

Welche Methoden braucht die Bildungsforschung? Eine fachdidaktische Perspektive

Die Frage, welche Forschungsmethoden eine bestimmte Disziplin bzw. ein bestimmtes Berufsfeld „braucht“ und demzufolge auch Gegenstand der Ausbildung sein müssen, ist sicher hochrelevant. Im Beitrag nehmen die Autoren, aus der Perspektive der Fachdidaktik (Physik), im Kern die Position ein, dass der Auswahl und Begründung von Methoden zwar eine zentrale Rolle im Forschungsprozess zukommt, gleichzeitig aber nicht im Vorhinein eine Festlegung auf bestimmte Methoden erfolgen kann, die das Forschungsfeld vermeintlich braucht bzw. nicht braucht. Sie leiten aus dieser Grundposition drei Thesen ab, die nach der Erläuterung von Vorannahmen den Beitrag strukturieren. Die Überlegungen basieren auf einem Statement von Claudia von Aufschnaiter in einer Podiumsdiskussion anlässlich eines Workshops zu Forschungsmethoden im November 2018 und greifen Diskussionsanregungen aus diesem Workshop auf. (DIPF/Orig.