Studies of patients afflicted by neurodegenerative diseases suggest that misfolded proteins spread through the brain along anatomically-connected networks, prompting progressive decline. Recently, mouse models have recapitulated the cell-to-cell transmission of pathogenic proteins and neuron death observed in patients. However, factors regulating spread of pathogenic proteins remain a matter of debate due to an incomplete understanding of how vulnerability functions in the context of spread. Here, we use quantitative pathology mapping in the mouse brain combined with network modeling to understand the spatiotemporal pattern of spread. α-Synuclein pathology patterns are well-described by a network model based on two factors—anatomical connectivity and endogenous α-Synuclein expression. The map and model allow assessment of selective vulnerability to α-Synuclein pathology development and neuron death. Finally, we use quantitative pathology to understand how the G2019S LRRK2 genetic risk factor impacts the spread and toxicity of α-Synuclein pathology.

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Neuronal Ceroid Lipofuscinoses (NCL) are a group of inherited neurodegenerative disorders with lysosomal pathology (CLN1-14). Recently, mutations in the DNAJC5/CLN4 gene, which encodes the presynaptic co-chaperone CSP were shown to cause autosomal-dominant NCL. Although 14 NCL genes have been identified, it is unknown if they act in common disease pathways. Here we show that two disease-associated proteins, CSPα and the depalmitoylating enzyme palmitoyl-protein thioesterase 1 (PPT1/CLN1) are biochemically linked. We find that in DNAJC5/CLN4 patient brains, PPT1 is massively increased and mis-localized. Surprisingly, the specific enzymatic activity of PPT1 is dramatically reduced. Notably, we demonstrate that CSP is depalmitoylated by PPT1 and hence its substrate. To determine the consequences of PPT1 accumulation, we compared the palmitomes from control and DNAJC5/CLN4 patient brains by quantitative proteomics. We discovered global changes in protein palmitoylation, mainly involving lysosomal and synaptic proteins. Our findings establish a functional link between two forms of NCL and serve as a springboard for investigations of NCL disease pathways.