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Cell-intrinsic properties determine susceptibility to neuronal degeneration


Intracellular accumulations of proteins such as α-synuclein or tau are found in various neurodegenerative disorders, for example in Parkinson's disease (α-synuclein) and Alzheimer's disease (tau). Mutations of these proteins can lead to neuronal cell death at a relatively young age in affected individuals. However, there are clear differences within the brain, i.e. some areas are more affected by protein deposits with subsequent cell death than others.


The question of whether primarily increased synthesis (or decreased degradation) of the pathologically altered synuclein and tau proteins leads to neurodegeneration or whether there is a preferential susceptibility of certain neurons due to different local or cellular properties (with the same amount of toxic proteins) has remained unresolved. Praschberger and colleagues, in a paper recently published in the high-impact journal Neuron, now show that susceptible from resilient neurons are indeed distinguished by cellular properties involving differences in mitochondrial activity (for synuclein) or synaptic organization and intracellular calcium homeostasis (for tau). To do this, they used gene expression data from single neurons in the human brain and wide-ranging analyses of over 200 different neuron types in the fruit fly (Drosophila) brain.


The authors showed that although α-synuclein and tau levels in Drosophila correlate across brain cell types, different neuronal circuits are affected by these proteins. Mapping of tau-associated vulnerability genes in the fly to tauopathy-relevant human brain regions clearly yielded cell types with preferential vulnerability, including dopaminergic neurons of substantia nigra and reelin-positive neurons of lamina II in entorhinal cortex. Furthermore, comparatively low α-synuclein expression in inhibitory (GABAergic) neurons was evident in human brain data sets, which may explain the typical absence of α-synuclein aggregates in these cells.


In conclusion, in humans, there is no clear correlation of α-synuclein and tau levels with neuronal vulnerability; however, in Drosophila models of α-synuclein and tauopathy, selective neuronal vulnerability can be observed at transcriptional, structural, and functional levels. Therefore, future treatment approaches in Parkinson's and Alzheimer's disease based on the analysis and use of resilience strategies of defined brain areas should be possible to identify.


Reference:


Praschberger R, Kuenen S, Schoovaerts N, ..., Poovathingal S, Verstreken P (2023) Neuronal identity defines α-synuclein and tau toxicity. Neuron 111:1577


Image credit: iStock/Dr_Microbe

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