Mark, J. R. | Search bioRxiv

bioRxiv2024

Peripheral immune cell response to stimulation stratifies Parkinson's disease progression from prodromal to clinical stages

The motor stage of idiopathic Parkinsons disease (iPD) can be preceded for years by a prodromal stage characterized by non-motor symptoms like REM sleep behavior disorder (RBD). Here, we show that multiple stages of iPD, including the pre-motor prodromal stage, can be stratified according to the inflammatory and immunometabolic responses to stimulation of peripheral blood mononuclear cells ex vivo. We identified increased stimulation-dependent secretion of TNF, IL-1{beta}, and IL-8 in monocytes from RBD patients and showed diminished proinflammatory cytokine secretion in monocytes and T cells in early and moderate stages of PD. Mechanistically, immune activation revealed deficits in CD8+ T-cell mitochondrial health in moderate PD, and relative mitochondrial health in CD8+ T cells was positively correlated with stimulation-dependent T-cell cytokine secretion across the PD spectrum. Dysregulated immunometabolism may drive peripheral inflammation and PD progression, and ex vivo stimulation-based assays have potential to reveal novel biomarkers for patient stratification and progression with immune endophenotypes.

neuroscience↗

bioRxiv2017

Distributed Rhythm Generators Underlie Caenorhabditis elegans Forward Locomotion

Coordinated rhythmic movements are ubiquitous in animal behavior. In many organisms, chains of neural oscillators underlie the generation of these rhythms. In C. elegans, locomotor wave generation has been poorly understood; in particular, it is unclear where in the circuit rhythms are generated, and whether there exists more than one such generator. We used optogenetic and ablation experiments to probe the nature of rhythm generation in the locomotor circuit. We found that multiple sections of forward locomotor circuitry are capable of independently generating rhythms. By perturbing different components of the motor circuit, we localize the source of secondary rhythms to cholinergic motor neurons in the midbody. Using rhythmic optogenetic perturbation we demonstrate bidirectional entrainment of oscillations between different body regions. These results show that, as in many other vertebrates and invertebrates, the C. elegans motor circuit contains multiple oscillators that coordinate activity to generate behavior.

neuroscience↗