Biology subjects

Brueggemann, N.

Publications and source records attributed to Brueggemann, N..

3 recordsLinked to original sources

bioRxiv2023

The R1441C-LRRK2 mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner

Considering age is the greatest risk factor for many neurodegenerative diseases, aging, in particular aging of the immune system, is the most underappreciated and understudied contributing factor in the neurodegeneration field. Genetic variation around the LRRK2 gene affects risk of both familial and sporadic Parkinsons disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein has been implicated in peripheral immune signaling, however, the effects of an aging immune system on LRRK2 function have been neglected to be considered. We demonstrate here that the R1441C mutation induces a hyper-responsive phenotype in macrophages from young female mice, characterized by increased effector functions, including stimulation-dependent antigen presentation, cytokine release, phagocytosis, and lysosomal function. This is followed by age-acquired immune cell exhaustion in a Lrrk2-kinase-dependent manner. Immune-exhausted macrophages exhibit suppressed antigen presentation and hypophagocytosis, which is also demonstrated in myeloid cells from R1441C and Y1699C-PD patients. Our novel findings that LRRK2 mutations confer immunological advantage at a young age but may predispose the carrier to age-acquired immune cell exhaustion have significant implications for LRRK2 biology and therapeutic development. Indeed, LRRK2 has become an appealing target in PD, but our findings suggest that more research is required to understand the cell-type specific consequences and optimal timing of LRRK2-targeting therapeutics. One Sentence SummaryThe R1441C-LRRK2 mutation causes an age-acquired immune cell exhaustion in macrophages in a sex-dependent manner

immunology↗

bioRxiv2020

Motor sequence learning deficits in idiopathic Parkinsons disease are associated with increased substantia nigra activity

Previous studies have shown that persons with Parkinsons disease (pwPD) share specific deficits in learning new sequential movements, but the neural substrates of this impairment remain unclear. In addition, the degree to which striatal dopaminergic denervation in PD affects the cortico-striato-cerebellar motor learning network remains unknown. We aimed to answer these questions using fMRI in 16 pwPD and 16 healthy age-matched control subjects while they performed an implicit motor sequence learning task. While learning was absent in both pwPD and controls assessed with reaction time differences between sequential and random trials, larger error-rates during the latter suggest that at least some of the complex sequence was encoded. Moreover, we found that while healthy controls could improve general task performance indexed by decreased reaction times across both sequence and random blocks, pwPD could not, suggesting disease-specific deficits in learning of stimulus-response associations. Using fMRI, we found that this effect in pwPD was correlated with decreased activity in the hippocampus over time. Importantly, activity in the substantia nigra (SN) and adjacent bilateral midbrain was specifically increased during sequence learning in pwPD compared to healthy controls, and significantly correlated with sequence-specific learning deficits. As increased SN activity was also associated (on trend) with higher doses of dopaminergic medication as well as disease duration, the results suggest that learning deficits in PD are associated with disease progression, indexing an increased drive to recruit dopaminergic neurons in the SN, however unsuccessfully. Finally, we found no differences between pwPD and controls in task modulation of the cortico-striato-cerebellar network. Notably, in both groups Bayesian model selection revealed cortico-cerebellar connections modulated by the task, suggesting that despite behavioral and activation differences, the same cortico-cerebellar circuitry is recruited for implementing the motor task.

neuroscience↗

bioRxiv2020

Barley shoot biomass responds strongly to N:P stoichiometry and intraspecific competition, whereas roots only alter their foraging

Background and AimsPlants respond to various environmental stimuli, and root systems are highly responsive to the availability and distribution of nutrients in the soil. Root system responses to the limitation of either nitrogen (N) or phosphorus (P) are well documented, but how the early root system responds to (co-) limitation of one (N or P) or both (N and P) in a stoichiometric framework is not well known despite its relevance in agriculture. In addition, how plant-plant competition (here intra-specific) alters plant responses to N:P stoichiometry is understudied. Therefore, we aimed to investigate the effects of N:P stoichiometry and competition on root system responses and overall plant performance. MethodsPlants (Hordeum vulgare L.) were grown in rhizoboxes for 24 days in the presence or absence of competition (three vs. one plant per rhizobox), and fertilized with different combinations of N:P (low N+low P, low N+high P, high N+low P, and high N+high P). Key ResultsShoot biomass was highest when both N and P were provided in high amounts. In competition, shoot biomass decreased on average by 22%. Interestingly, N:P stoichiometry and competition had no clear effect on root biomass. However, we found distinct root responses in relation to biomass allocation across depths. Specific root length depended on the identity of limiting nutrient (N or P) and presence/absence of competition. Plants rooted deeper when N was the most limiting compared to shallower rooting when P was the most limiting nutrient. ConclusionsOverall, our study sheds light on the early plant responses to plant-plant competition and stoichiometric availability of two macronutrients most limiting plant performance. With low N and P availability during early growth, higher investments in root system development can significantly trade off with aboveground productivity, and strong intra-specific competition can further strengthen such effects.

plant biology↗