Biology subjects

Kuenen, S.

Publications and source records attributed to Kuenen, S..

3 recordsLinked to original sources

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↗

bioRxiv2022

EndophilinA-dependent coupling between activity-dependent calcium influx and synaptic autophagy is disrupted by a Parkinson-risk mutation

Neuronal activity and neurotransmitter release cause use-dependent decline in protein function. However, it is unclear how this is coupled to local protein turnover and quality control mechanisms. Here we show that the endocytic protein Endophilin-A (EndoA/ENDOA1) couples activity-induced calcium influx to synaptic autophagy and neuronal survival. We identify single mutations in the EndoA flexible region that either increases EndoA diffusion and promotes autophagosome formation in the absence of calcium, or immobilizes EndoA and blocks autophagy, even in the presence of calcium. Hence, the EndoA flexible region is a switch that responds to calcium, regulating EndoA nanoscale synaptic organization and association with autophagosomes driving their formation. Interestingly, a pathogenic variant in the human ENDOA1 variable region that confers risk to Parkinsons disease (PD), also confines ENDOA1 to the synaptic plasma membrane and equally blocks autophagy in flies in vivo and in induced human neurons. Thus, our work reveals a mechanism neurons use to connect neuronal activity to local protein turnover by autophagy, which is critical for neuronal survival.

neuroscience↗

bioRxiv2022

Parkinson mutations in DNAJC6 cause lipid defects and neurodegeneration that are rescued by Synj1

Recent evidence links dysfunctional lipid metabolism to the pathogenesis of Parkinsons disease, but the mechanisms are not resolved. Here, we created a new Drosophila knock-in model of DNAJC6/Auxilin and find that the pathogenic mutation causes synaptic dysfunction, neurological defects and neurodegeneration, as well as specific lipid metabolism alterations. In these mutants membrane lipids containing long-chain polyunsaturated fatty acids, including phosphatidylinositol lipid species that are key for synaptic vesicle recycling and organelle function are reduced. Overexpression of another protein mutated in Parkinsons disease, Synaptojanin-1, known to bind and synthesize specific phosphoinositides, strongly rescues the DNAJC6/Auxilin neuronal defects and neurodegeneration. Our work reveals a functional relation between two proteins mutated in Parkinsons disease and implicates deregulated phosphoinositide metabolism in the maintenance of neuronal integrity and neuronal survival in Parkinsonism.

cell biology↗