bioRxiv Science⌕ Search

Biology subjects

Rush, T.

Publications and source records attributed to Rush, T..

3 recordsLinked to original sources

Differences in spore size and atmospheric survival shape stark contrasts in the dispersal dynamics of two closely related fungal pathogens

A frequently ignored but critical aspect of microbial dispersal is survival in the atmosphere. We exposed spores of two closely related, morphologically dissimilar, and economically important fungal pathogens to typical atmospheric environments and modeled their movement in the troposphere. We first measured the mortality of Alternaria solani and A. alternata conidia exposed to ranges of solar radiation, relative humidity, and temperature. We then measured survival in an advantageous environment over 12 days. A. solani conidia are nearly 10 times larger than A. alternata conidia and most die after 24 hours. By contrast, over half of A. alternata conidia remained viable at 12 days. The greater viability of the smaller spores is counterintuitive as larger spores are assumed to be more durable. To elucidate the consequences of survival rates for dispersal, we deployed models of atmospheric spore movement across North American. We predict 99% of the larger A. solani conidia settle within 24 hours, with a maximum dispersal distance of 100 km. By contrast, most A. alternata conidia remain airborne for more than 12 days and long-distance dispersal is possible, e.g., from Wisconsin to the Atlantic Ocean. We observe that the larger conidia of A. solani survive poorly but also land sooner and move over shorter distances as compared to the smaller conidia of A. alternata. Our data relating larger spore size to poorer survival in the atmosphere and shorter distances travelled likely translate to other fungal species and highlight the potential for starkly different dispersal dynamics among even closely related fungi.

microbiology↗

Alzheimer's disease risk gene BIN1 induces Tau-dependent network hyperexcitability

Genome-wide association studies identified the BIN1 locus as a leading modulator of genetic risk in Alzheimers disease (AD). One limitation in understanding BIN1s contribution to AD is its unknown function in the brain. AD-associated BIN1 variants are generally noncoding and likely change expression. Here, we determined the effects of increasing expression of the major neuronal isoform of human BIN1 in cultured hippocampal neurons. Higher BIN1 induced network hyperexcitability on multielectrode arrays, increased frequency of synaptic transmission, and elevated calcium transients, indicating that increasing BIN1 drives greater neuronal activity. In exploring the mechanism of these effects on neuronal physiology, we found that BIN1 interacted with L-type voltage-gated calcium channels (LVGCCs) and that BIN1-LVGCCs interactions were modulated by Tau in vitro and in vivo. Finally, Tau reduction prevented BIN1-induced network hyperexcitability. These data shed light on BIN1s neuronal function and suggest that it may contribute to Tau-dependent hyperexcitability in AD.

neuroscience↗

A peptide inhibitor of Tau-SH3 interactions ameliorates amyloid-β toxicity

The microtubule-associated protein Tau is strongly implicated in Alzheimers disease (AD) and aggregates into neurofibrillary tangles in AD. Genetic reduction of Tau is protective in several animal models of AD and cell culture models of amyloid-{beta} (A{beta}) toxicity, making it an exciting therapeutic target for treating AD. A variety of evidence indicates that Taus interactions with Fyn kinase and other SH3 domain-containing proteins, which bind to PxxP motifs in Taus proline-rich domain, may contribute to AD deficits and A{beta} toxicity. Thus, we sought to determine if inhibiting Tau-SH3 interactions ameliorates A{beta} toxicity. We developed a peptide inhibitor of Tau-SH3 interactions and a proximity ligation assay (PLA)-based target engagement assay. Then, we used membrane trafficking and neurite degeneration assays to determine if inhibiting Tau-SH3 interactions ameliorated A{beta} oligomer (A{beta}o)-induced toxicity in primary hippocampal neurons from rats. We verified that Tau reduction ameliorated A{beta}o toxicity in neurons. Using PLA, we identified a peptide inhibitor that reduced Tau-SH3 interactions in HEK-293 cells and primary neurons. This peptide reduced Tau phosphorylation by Fyn without affecting Fyns kinase activity state. In primary neurons, endogenous Tau-Fyn interaction was present primarily in neurites and was reduced by the peptide inhibitor, from which we inferred target engagement. Reducing Tau-SH3 interactions in neurons ameliorated A{beta}o toxicity by multiple outcome measures, namely A{beta}o-induced membrane trafficking abnormalities and neurite degeneration. Our results indicate that Tau-SH3 interactions are critical for A{beta}o toxicity and that inhibiting them is a promising therapeutic target for AD.

neuroscience↗