Biology subjects

Summers, B.

Publications and source records attributed to Summers, B..

3 recordsLinked to original sources

bioRxiv2026

Intrastriatal injection of amplified Lewy body dementia (LBD) fibrils in mice results in accumulation of fibrils with LBD structure and neurodegeneration

The defining neuropathologic feature of Lewy body dementia (LBD) and Parkinson's disease (PD) is alpha-synuclein (Asyn) fibril accumulation in Lewy bodies (LBs) and Lewy neurites (LNs). Recently, we developed a method to amplify Asyn fibrils derived from human post-mortem LBD brain tissue and determined that the structure of amplified Asyn fibrils is highly similar to the structure of fibrils directly isolated from LBD brain tissue. We examined whether injection of these fibrils into humanized Asyn mice recapitulates pathologic Asyn fibril accumulation with human LBD Asyn fibril structure. We utilized mice containing a null allele in the mouse Snca gene and a human SNCA transgene. Intrastriatal injection of amplified Asyn fibrils derived from 3 different LBD autopsy cases resulted in cytoplasmic and neuritic phospho-Asyn accumulation in the striatum, cortex, and amygdala bilaterally at 3mpi. Fibril injections produced a reduction in the number of dopaminergic neurons in the substantia nigra, with LB-like inclusions in surviving neurons, and produced impaired sensorimotor function as measured on the accelerating rotarod test. Fibril accumulation increased 3.6-fold between 1 and 3 months post-injection (mpi) and was relatively stable between 3 and 5 mpi. We amplified fibrils from mouse brain tissue 5 mpi and collected single-particle cryo-EM data. High resolution 3D structural information could not be obtained because of the lack of helical twist, but comparison of the cryo-EM 2D class averages with those derived from amplified fibrils prepared from human LBD tissue revealed multiple matching classes, indicating that the Lewy fold is maintained in the fibrils that accumulate in mouse brain tissue. Our findings demonstrate an approach to model the accumulation of Asyn fibrils with LBD structure in mice, providing a platform for investigating disease mechanisms, imaging biomarkers, and therapeutics targeting Asyn in PD/LBD.

neuroscience↗

bioRxiv2023

Lymphatic Dysfunction Models an Autoimmune Emphysema Phenotype of Chronic Obstructive Pulmonary Disease

Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous disease that is characterized by many clinical phenotypes. One such phenotype of COPD is defined by emphysema, pathogenic lung tertiary lymphoid organs (TLOs), and autoantibody production. We have previously shown that lymphatic dysfunction can cause lung TLO formation and lung injury in mice. We now sought to uncover whether underlying lymphatic dysfunction may be a driver of lung injury in cigarette smoke (CS)-induced COPD. We found that lung TLOs in mice with lymphatic dysfunction produce autoantibodies and are associated with a lymphatic endothelial cell subtype that expresses antigen presentation genes. Mice with underlying lymphatic dysfunction develop increased emphysema after CS exposure, with increased size and activation of TLOs. CS further increased autoantibody production in mice with lymphatic dysfunction. B-cell blockade prevented TLO formation and decreased lung injury after CS in mice with lymphatic dysfunction. Using tissue from human COPD patients, we also found evidence of a lymphatic gene signature that was specific to patients with emphysema and prominent TLOs compared to COPD patients without emphysema. Taken together, these data suggest that lymphatic dysfunction may underlie lung injury in a subset of COPD patients with an autoimmune emphysema phenotype.

pathology↗

bioRxiv2023

Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue

The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. We developed and validated a novel method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and used solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. Amplified LBD Asyn fibrils comprise two protofilaments with pseudo-21 helical screw symmetry, very low twist and an interface formed by antiparallel beta strands of residues 85-93. The fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted from LBD tissue. These results expand the structural landscape of LBD Asyn fibrils and inform further studies of disease mechanisms, imaging agents and therapeutics targeting Asyn.

neuroscience↗