Evaluating the performance of polygenic risk profiling across diverse ancestry populations in Parkinson’s diseaseon
Objective: This study aims to address disparities in risk prediction by evaluating the performance of polygenic risk score (PRS) models using the 90 risk variants across 78 independent loci previously linked to Parkinson’s disease (PD) risk across seven diverse ancestry populations.
NeuroBooster Array: A genome-wide genotyping platform to study neurological disorders across diverse populationson
Preprint: People envisage this valuable tool will standardize genetic studies in neurological disorders across different ancestral groups, allowing researchers to perform genetic research inclusively and at a global scale.
Preprint: The authors studied 709 persons with PD, which show that the non-coding GBA1 rs3115534 risk variant is associated with increased RBD symptomatology in Nigerians with PD. Further research is required to assess association with polysomnography-defined RBD.
Our results demonstrate that GABAARs can work in concert with iGluRs to excite adult SPNs when they are in the resting down-state, suggesting that their inhibitory role is limited to brief periods near spike threshold. This state-dependence calls for a reformulation of the role intrastriatal GABAergic circuits.
Mutations in GPNMB associated with Amyloid cutis dyschromica alter intracellular trafficking and processing of GPNMBon
Preprint: Amyloid cutis dyschromica (ACD) is a rare skin condition characterized by focal areas of hyperpigmentation with hypopigm. This work highlights previously undescribed cellular characteristics of GPNMB missense mutations implicated in ACD and helps to better inform the clinically observed phenotypes, as well as underscore GPNMB’s role at melanosomes.
Published: The authors formulate outstanding research questions regarding the role of polyamines in PD, their potential as PD biomarkers, and possible therapeutic strategies for PD targeting polyamine homeostasis.
Published: Future applications of rapid lysosomal isolation techniques are likely to greatly enhance our understanding of lysosomal dysfunction in rare and common neurodegeneration causes.
Modelling human brain-wide pigmentation in rodents recapitulates age-related multisystem neurodegenerative deficitson
In parallel to progressive human-like neuromelanin pigmentation, these animals display age-related neuronal dysfunction and degeneration affecting numerous brain circuits and body tissues, linked to motor and non-motor deficits, reminiscent of early neurodegenerative stages. This model may open new research avenues in the field of brain aging and neurodegeneration.
Adult-specific Reelin expression alters striatal neuronal organization: implications for neuropsychiatric disorderson
The authors increased Reelin levels might modulate the numbers of striatal interneurons and the density of the nigrostriatal dopaminergic projections, suggesting that these changes may be involved in the protection of Reelin against neuropsychiatric disorders. View original preprint.
Preprint: The authors evaluated Gauchian in 90 Sanger-sequenced patients with GD and five GBA1 heterozygotes using the software tool Gauchian to identify GBA1 variants from whole genome sequencing. While Gauchian genotyped most patients correctly, this limits Gauchian's utility in variant screening and precluding its use in diagnostics.
Published: The team identified repeated blows to head in sports/combat as a potential new risk factor. 23% of PD cases in females were attributable to pesticides/herbicides exposure, and 30% of PD in males were attributable to pesticides/herbicides, military-related chemical exposures, and repeated blows to the head, and therefore could have potentially been prevented. View original preprint.
Published: The team proposes intra-cell-type heterogeneity as a new mechanism for sculpting the computational properties of local circuits of excitatory and inhibitory spiking neurons, permitting the same canonical microcircuit to be tuned for diverse computational tasks. This work may serve as the basis for examining the effects of neural heterogeneity in more specific brain systems, such as the basal ganglia. View original preprint.
Published: The main purpose of the paper is to demonstrate how these three tools can support the computational/mathematical modeling of neural systems with a variety of numerical methods that are well tested and documented. Thus, the authors present a powerful tool kit for computational/mathematical approaches to studying the dynamics and functions of complex neural systems such as the basal ganglia. View original preprint.
Preprint: This sensitive, computationally efficient approach enables fluorescent puncta and cellular features to be distinguished in cellular and tissue environments with a sensitivity down to the level of the single protein.
To understand PD-associated sleep-wake abnormalities, a new progressive model of PD - the MCI-Park mouse - was studied. Near the transition to the parkinsonian state, these mice exhibited significantly altered sleep-wake regulation, including increased wakefulness, decreased non-rapid eye movement (NREM) sleep, increased sleep fragmentation, reduced rapid eye movement (REM) sleep, and altered EEG activity patterns.
While the basal ganglia circuit model underpinning the notion that striatal dopamine (DA) depletion was the critical determinant of network pathophysiology underlying the motor symptoms of Parkinson’s disease, the hypothesis itself has never been directly tested. It is time for a new model of the network determinants of motor disability in PD.
α-Synuclein pathology disrupts mitochondrial function in dopaminergic and cholinergic neurons at-risk in Parkinson’s diseaseon
The mechanisms by which intracellular aSYN pathology contributes to dysfunction and degeneration of neurons in the brain are still unclear. Genetic and physiological methods were used to monitor mitochondrial function in substantia nigra pars compacta (SNc) dopaminergic and pedunculopontine nucleus (PPN) cholinergic neurons after stereotaxic injection of aSYN pre-formed fibrils (PFFs) into the mouse brain.
Published: Reinforcement mechanism promotes not only reinforcement, but gradual refinement of the entire behavioral repertoire to assign credit to specific actions and action sequences that lead to dopamine release.
Scalable, flexible carbon fiber electrode thread arrays for three-dimensional probing of neurochemical activity in deep brain structures of rodentson
The authors' CFET array has the potential to unlock a wide range of applications, from uncovering the role of neuromodulators in synaptic plasticity, to addressing critical safety barriers in clinical translation towards diagnostic and adaptive treatment in Parkinson’s disease and major mood disorders.
Synchronous measurements of extracellular action potentials and neurochemical activity with carbon fiber electrodes in nonhuman primateson
Synchronous measures of spike and dopamine signals displayed contrasting relations to the behavioral task parameters, as taken from the small set of representative data, suggesting a complex relationship between these two modes of neural signaling.