Biology subjects

Nachman, E.

Publications and source records attributed to Nachman, E..

3 recordsLinked to original sources

bioRxiv2024

Soma-centered control of synaptic autophagy by Rab39-regulated anterograde trafficking of Atg9

Presynaptic terminals can be located far from the neuronal cell body and are thought to independently regulate protein and organelle turnover. In this work, we report a soma-centered mechanism that regulates autophagy-driven protein turnover at distant presynaptic terminals in Drosophila. We show that this system is regulated by Rab39, whose human homolog is mutated in Parkinsons disease. Although Rab39 is localized in the soma, its loss of function causes increased autophagy at presynaptic terminals, resulting in faster synaptic protein turnover and neurodegeneration. Using a large-scale unbiased genetic modifier screen, we identified genes encoding cytoskeletal and axonal organizing proteins, including Shortstop (Shot), as suppressors of synaptic autophagy. We demonstrate that Rab39 controls Shot-and Unc104/KIF1a-mediated transport of autophagy-related Atg9 vesicles to synapses. Under starvation conditions, Rab39 in the soma shifts its localization from endosomes to lysosomes, thereby controlling the availability of Atg9 vesicles for trafficking to synapses. Our findings indicate that Rab39-mediated trafficking in the soma orchestrates a cross-compartmental mechanism that regulates the abundance of autophagy at synapses.

neuroscience↗

bioRxiv2022

Neuronal identity defines a-synuclein and tau toxicity

Pathogenic -synuclein and tau are critical drivers of neurodegeneration and their mutations cause neuronal loss in patients. Whether the underlying preferential neuronal vulnerability is a cell-type intrinsic property or a consequence of increased expression levels is an open question. Here, we explore cell-type specific -synuclein and tau expression in human brain datasets and use deep phenotyping as well as brain-wide single-cell RNA sequencing of >200 live neuron types in fruit flies to ask which cellular environments react most to -synuclein or tau toxicity. We detect phenotypic and transcriptomic evidence of differential neuronal vulnerability independent of -synuclein or tau expression levels. Comparing vulnerable with resilient neurons enabled us to identify molecular signatures associated with these differential responses. We used these to verify, and then predict resilient and vulnerable neuron subtypes in human brains. This confirms substantia nigra dopaminergic neurons to be sensitive to -synuclein, and we predict pathogenic tau vulnerable and protected cortical neuron subtypes. Our work indicates that cellular determinants confer selective vulnerability to specific types of amyloid toxicity, thus paving the way to leverage neuronal identity to uncover modifiers of neurodegeneration-associated toxic proteins.

neuroscience↗

bioRxiv2019

Disassembly of Tau fibrils by the human Hsp70 disaggregation machinery generates small seeding-competent species

The accumulation of amyloid Tau aggregates is implicated in Alzheimers disease and other Tauopathies. Molecular chaperones are known for their function in maintaining protein homeostasis by preventing the formation or promoting the disaggregation of amorphous and amyloid protein aggregates. Here we show that an ATP-dependent human chaperone system disassembles Tau fibrils in vitro. This function is mediated by the core chaperone Hsc70, assisted by specific co-chaperones, in particular class B J-domain proteins and an Hsp110-type NEF. Recombinant fibrils assembled from all six Tau isoforms as well as Sarkosyl-resistant Tau aggregates extracted from cell culture were processed by the Hsp70 disaggregation machinery, demonstrating the ability of this machinery to recognize a broad range of Tau aggregates. Chaperone treatment released monomeric, and small oligomeric Tau species, which induced the aggregation of self-propagating Tau species in a Tau cell culture model. We infer from these results that the activity of the Hsp70 disaggregation machinery is a double-sided sword as it attempts to eliminate Tau amyloids but with the price of generating new seeds. The Hsp70 disaggregase therefore has a crucial function in the Tau propagation cycle, rendering it a potential drug target in Tauopathies.

molecular biology↗