Papers by Johanna eickholt
The brain of mammals lacks a significant ability to regenerate neurons and is thus particularly v... more The brain of mammals lacks a significant ability to regenerate neurons and is thus particularly vulnerable. To protect the brain from injury and disease, damage control by astrocytes through astrogliosis and scar formation is vital. Here, we show that brain injury triggers an ad hoc upregulation of the actin-binding protein Drebrin (DBN) in astrocytes, which is essential for the formation and maintenance of glial scars in vivo. In turn, DBN loss leads to defective glial scar formation and excessive neurodegeneration following mild brain injuries. At the cellular level, DBN switches actin homeostasis from ARP2/3-dependent arrays to microtubule-compatible scaffolds and facilitates the formation of RAB8-positive membrane tubules. This injury-specific RAB8 membrane compartment serves as hub for the trafficking of surface proteins involved in astrogliosis and adhesive responses, such as β1-integrin. Our work identifies DBN as pathology-specific actin regulator, and establishes DBN-depend...
The intermediate filament protein vimentin is essential for axonotrophic effects of Clostridium botulinum C3 exoenzyme
Journal of Neurochemistry, 2016
The type III intermediate filament protein vimentin was recently identified to mediate binding an... more The type III intermediate filament protein vimentin was recently identified to mediate binding and uptake of Clostridium botulinum C3 exoenzyme (C3bot) in two cell lines. Here, we used primary neuronal cultures from vimentin knockout (Vim−/−) mice to study the impact of vimentin on axonal growth and internalization of C3bot. In contrast to wild type, vimentin knockout neurons were insensitive to C3bot. Application of extracellular vimentin to Vim−/− neurons completely restored the growth‐promoting effects of C3bot. In line with this uptake of C3bot into Vim−/− neurons was strongly decreased resulting in reduced ADP‐ribosylation of RhoA and B as detected by an antibody recognizing selectively ADP‐ribosylated RhoA/B. Again, uptake of C3bot into Vim−/− neurons was rescued by addition of extracellular vimentin. In addition, in purified embryonic stem cell‐derived motor neurons that are devoid of glial cells C3bot elicited axonotrophic effects confining neuronal vimentin as a binding partner.
Defective actin dynamics in dendritic spines: cause or consequence of age-induced cognitive decline?
Biological Chemistry, 2016
Ageing is a complex deteriorating process that coincides with changes in metabolism, replicative ... more Ageing is a complex deteriorating process that coincides with changes in metabolism, replicative senescence, increased resistance to apoptosis, as well as progressive mitochondria dysfunction that lead to an increase production and accumulation of reactive oxygen species (ROS). Although controversy on the paradigm of the oxidative damage theory of ageing exists, persuasive studies in Caenorhabditis elegans and yeast have demonstrated that manipulation of ROS can modify the process of ageing and influences the damage of proteins, lipids and DNA. In neurons, ageing impacts on the intrinsic neuronal excitability, it decreases the size of neuronal soma and induces the loss of dendrites and dendritic spines. The actin cytoskeleton is an abundant and broadly expressed system that plays critical functions in many cellular processes ranging from cell motility to controlling cell shape and polarity. It is thus hardly surprising that the expression and the function of actin in neurons is cruc...
PLOS Biology, 2015
The branching behaviors of both dendrites and axons are part of a neuronal maturation process ini... more The branching behaviors of both dendrites and axons are part of a neuronal maturation process initiated by the generation of small and transient membrane protrusions. These are highly dynamic, actin-enriched structures, collectively called filopodia, which can mature in neurons to form stable branches. Consequently, the generation of filopodia protrusions is crucial during the formation of neuronal circuits and involves the precise control of an interplay between the plasma membrane and actin dynamics. In this issue of PLOS Biology, Hou and colleagues identify a Ca 2+ /CaM-dependent molecular machinery in dendrites that ensures proper targeting of branch formation by activation of the actin nucleator Cobl.
Filopodia formation in five steps
<p>1. Under resting conditions, actin nucleators (blue and green crosses), filament bundlin... more <p>1. Under resting conditions, actin nucleators (blue and green crosses), filament bundling and crosslinking proteins (grey crosses), and membrane curvature–sensing proteins (purple and orange curved lines) reside in the cytosol and preserve a base-line level of filamentous (F-) actin (red lines). Black dots denote plasma membrane microdomains rich in specific lipids and transmembrane proteins. 2. Upon signaling (e.g., increases in Ca<sup>2+</sup> in the cytosol or activation of growth factor induced Phosphatidylinositol-4,5-bisphosphate (PIP2)-Phosphatidylinositol-3,4,5-trisphosphate (PIP3) turnover), nucleators are activated and, together with elongation factors, promote rapid actin polymerization and actin patch formation. 3. Filaments extend rapidly towards the membrane, and changes in membrane curvature are sensed and/or induced by curvature-sensing proteins. 4. A growing filopodium has established a mixture of unbundled and bundled or crosslinked actin filaments. It is conceivable that different sets of nucleators and elongators may contribute to increased actin polymerization. Other proteins that uncap or cap barbed ends or proteins that sever filaments at the root of filopodia may regulate filament turnover during this process. 5. In a “mature” filopodium, additional signals may guide microtubule invasion in order to stabilize the nascent filopodium into a branch.</p
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Papers by Johanna eickholt