Output Catalog
ASAP is committed to accelerating the pace of discovery and informing a path to a cure for Parkinson’s disease through collaboration, research-enabling resources, and data sharing. We’ve created this catalog to showcase the research outputs and tools developed by ASAP-funded programs.
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Microbes and Parkinson’s Disease: from associations to mechanisms
Several microbes, including viruses, bacteria, and fungi, have been associated with an increased risk of PD in humans. Microbial infections can induce similar common pathways that are associated with PD, including systemic inflammatory responses,…
LRRK2 regulates the activation of the unfolded protein response and antigen presentation in macrophages during inflammation
Absence of PINK1 leads to MitAP over-activation engaging autoimmune mechanisms. This pathway is induced by TLR4, cGAS-STING, and UPR activation in response to inflammatory signals. LRRK2 and STING regulate transition from innate to adaptive immunity
Synaptotagmin-1-dependent phasic axonal dopamine release is dispensable for basic motor behaviors in mice
In Parkinson’s disease (PD), motor dysfunctions only become apparent after extensive loss of DA innervation. This resilience has been hypothesized to be due to the ability of many motor behaviors to be sustained through a diffuse basal tone of DA;…
The calcium sensor synaptotagmin-1 is critical for phasic axonal dopamine release in the striatum and mesencephalon, but is dispensable for basic motor behaviors in mice
In this work, we conditionally deleted the calcium sensor synaptotagmin-1 (Syt1) in DA neurons (cKODA mice) to abrogate most activity-dependent axonal DA release in the striatum and mesencephalon. Syt1 cKODA mice showed intact performance in…
MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death
These data place mitochondria-to-lysosome transport as a driver of pyroptosis and link multiple PD proteins along a common inflammatory pathway.
Comparative analysis of methods to reduce activation signature gene expression in PBMCs
Preserving the in vivo cell transcriptome is essential for accurate profiling, yet factors during cell isolation including time ex vivo and temperature induce artifactual gene expression, particularly in stress-responsive immune cells. In this…
Modeling gene-environment interactions in Parkinson’s Disease: Helicobacter pylori infection of Pink1-/- mice induces CD8 T cell-dependent motor and cognitive dysfunction.
Here, we demonstrate in a mouse model deficient in the PD-associated gene Pink, that infection with the human PD-associated gastric bacterium Helicobacter pylori leads to development of motor and cognitive signs resembling prodromal features of PD.
Adoptive transfer of mitochondrial antigen-specific CD8+ T-cells in mice causes parkinsonism and compromises the dopamine system
By adoptively transferring mitochondrial peptide-specific CD8+ T cells into WT and PINK1 KO mice, we find that this leads to L-DOPA-reversible motor impairment and to robust loss of DA neurons and axonal markers in the striatum in both PINK KO and WT
PINK1 deficiency rewires early immune responses in a mouse model of Parkinson’s disease triggered by intestinal infection
Using single-cell RNAseq in our PINK KO mouse model, we demonstrate that peripheral myeloid cells are the earliest highly dysregulated immune cell type followed by an aberrant T cell response shortly after infection.
Characterizing enteric neurons in dopamine transporter (DAT)-Cre reporter mice reveals dopaminergic subtypes with dual-transmitter content
Using a reporter mouse line expressing tdTomato under control of DAT promoter in the gut and single cell sequencing we uncovered a novel population of DA neurons unique to the ENS which was ChAT/DAT-tdTomato-immunoreactive and expressed Grp, Calcb.
LRRK2G2019S acts as a dominant interfering mutant in the context of iron overload
Using a model macrophage cell line we showed that LRRK2-G2019S mutation affects iron homeostasis by dysregulating iron-related proteins and blocking ferritinophagy in iron overload conditions, suggesting a role in iron dysregulation in PD.
A single Citrobacter rodentium infection in Pink1 knockout and wild type mice leads to regional blood-brain-barrier perturbation and glial activation without dopamine neuron axon terminal loss
We tested whether a gut infection causes blood-brain barrier permeability and brain inflammation. Results showed increased BBB permeability in specific brain regions at 26 days while tight-junction and dopamine related proteins remained unchanged
Lrrk2 G2019S mutation incites increased cell-intrinsic neutrophil effector functions and intestinal inflammation in a model of infectious colitis
Using single cell RNA sequencing, we demonstrate that LRRK2 G2019S is associated with an increased neutrophil presence in the colonic lamina propria during infection, Th17 skewing, upregulated Il17a, and greater colonic pathology.
Myeloid PINK1 represses mtDNA release and immune signaling that impacts neuronal pathology in patient-derived idiopathic PD models
PINK1 represses mtDNA release and STING/NF-κB activation in peripheral macrophages of PD model laying the foundation for understanding PINK1-related peripheral mechanisms in idiopathic PD and providing targets for further therapy development
