Dysfunction of Motor Cortices in Parkinson’s disease
By onIn this review, the authors discuss PD-related changes in frontal cortical motor regions, focusing on neuropathology, changes in neurotransmission, and altered network interactions.
R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations
By onLRRK2 mutations are closely associated with Parkinson’s disease (PD). Convergent evidence suggests that LRRK2 regulates striatal function. Here, by using knock-in mouse lines expressing the two most common LRRK2 pathogenic mutations—G2019S and R1441C—we investigated how LRRK2 mutations altered striatal physiology. While we found that both R1441C and G2019S mice displayed reduced nigrostriatal dopamine release, hypoexcitability in indirect-pathway striatal projection neurons, and alterations associated with an impaired striatal-dependent motor learning were observed only in the R1441C mice. We also showed that increased synaptic PKA activities in the R1441C and not G2019S mice underlie the specific alterations in motor learning deficits in the R1441C mice. In summary, our data argue that LRRK2 mutations’ impact on the striatum cannot be simply generalized. Instead, alterations in electrochemical, electrophysiological, molecular, and behavioral levels were distinct between LRRK2 mutations. Our findings offer mechanistic insights for devising and optimizing treatment strategies for PD patients.
Polygenic Parkinson’s Disease Genetic Risk Score as Risk Modifier of Parkinsonism in Gaucher Disease
By onBiallelic pathogenic variants in GBA1 are the cause of Gaucher disease (GD) type 1 (GD1), a lysosomal storage disorder resulting from deficient glucocerebrosidase. Heterozygous GBA1 variants are also a common genetic risk factor for Parkinson's disease (PD). GD manifests with considerable clinical heterogeneity and is also associated with an increased risk for PD. The objective of this study was to investigate the contribution of PD risk variants to risk for PD in patients with GD1.
Adult-Onset Deletion of ATP13A2 in Mice Induces Progressive Nigrostriatal Pathway Dopaminergic Degeneration and Lysosomal Abnormalities
By onMutations in ATP13A2 gene can cause familial Parkinson's disease. Deleting ATP13A2 in adult mice leads to dopaminergic nerve terminal loss and neuronal degeneration, mimicking symptoms of ATP13A2-related neurodegenerative diseases.
Tagless LysoIP for immunoaffinity enrichment of native lysosomes from clinical samples
By onHere, the authors report the development of the tagless LysoIP method to enable rapid enrichment of lysosomes from clinical samples and human cell lines.
Cell-type-directed design of synthetic enhancers
By onWe show that deep learning models can be used to design synthetic, cell-type-specific enhancers, starting from random sequences, and that this optimization process allows detailed tracing of enhancer features at single-nucleotide resolution.
Concerning neuromodulation as treatment of neurological and neuropsychiatric disorder: Insights gained from selective targeting of the subthalamic nucleus, para-subthalamic nucleus and zona incerta in rodents
By onNeuromodulation, such as deep brain stimulation, is advancing as a clinical intervention in neurological and neuropsychiatric disorders, including Parkinson´s disease. Here, the authors review current literature in the pre-clinical research fields.
Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain
By onMutations in LRRK2 and PINK1 are linked to Parkinson’s disease. Loss of PINK1 doesn't affect LRRK2-mediated Rab phosphorylation. Both genes impair ciliogenesis through parallel pathways, suggesting a common therapeutic strategy for PD.
Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson’s disease
By onThe authors developed an optimized pipeline for single-nucleus RNA sequencing (snRNA-seq) and generated a high-resolution hierarchically organized map revealing 20 molecularly distinct DA neuron subtypes.
Rapid modulation of striatal cholinergic interneurons and dopamine release by satellite astrocytes
By onThe authors found very rapid modulation of dopamine release at sub-second timescales, mediated by changes to acetylcholine signalling, and a surprising cell-to-cell “satellite” configuration of astrocytes next to striatal cholinergic interneurons.
Targeted micro-fiber arrays for measuring and manipulating localized multi-scale neural dynamics over large, deep brain volumes during behavior
By onThe authors designed a new micro-fiber array approach capable of chronically measuring and optogenetically manipulating local dynamics across over 100 targeted locations simultaneously in head-fixed and freely moving mice.
An axonal brake on striatal dopamine output by cholinergic interneurons
By onDepolarization of axons is crucial for triggering neurotransmitter release. Cholinergic interneurons and nicotinic receptors in the striatum interrupt this process, causing a temporary suppression of dopamine release.
The integrated stress response in brain diseases: A double-edged sword for proteostasis and synapses
By onThis review article discusses the role of ISR on the synaptic plasticity in brain disorders as well as its potential as a therapeutic target to improve circuit function
α-Synuclein overexpression and the microbiome shape the gut and brain metabolome in mice
By onThe authors quantitatively profiled nearly 630 metabolites in the gut, plasma and brain of α-synuclein-overexpressing mice with or without associated microbiota, finding tissue-specific changes driven by genotype, microbiome, and their interaction.
SynBot is an open-source image analysis software for automated quantification of synapses
By onSynapses are crucial for brain function. SynBot, an open-source software, automates synapse analysis using advanced algorithms to improve accuracy and reproducibility in studying synaptic phenotypes
RAB32 Ser71Arg in autosomal dominant Parkinson’s disease: linkage, association, and functional analyses
By onRAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. Here, the authors explore genetic variability in RAB GTPases within cases of familial Parkinson's disease.
Selective dopaminergic neurotoxicity modulated by inherent cell-type specific neurobiology
By onThis review article focuses on the key biological features of DAergic neurons that increase neurotoxicant susceptibility
Excessive firing of dyskinesia-associated striatal direct pathway neurons is gated by dopamine and excitatory synaptic input
By on-FosTRAP captures striatal neurons activated in levodopa-induced dyskinesia -Levodopa evokes high firing rates in TRAPed direct pathway striatal neurons (dMSNs) -TRAPed dMSNs show enhanced dopamine sensitivity and excitatory synaptic input
Autophagy preferentially degrades non-fibrillar polyQ aggregates.
By onProteins with expanded polyQ repeats form aggregates in neurodegenerative diseases. Autophagy struggles to clear these aggregates due to difficulty interacting with fibrillar structures, suggesting a need for new strategies to improve clearance.
Parkinsonism Sac domain mutation in Synaptojanin-1 affects ciliary properties in iPSC-derived dopaminergic neurons
By onWe show that a mutation in SJ1 that causes early-onset Parkinsonism affects the cilia of iPSC-derived DA neurons. Cilia are longer and show an accumulation of calcium channels and ubiquitinated proteins relative to control neurons, suggesting an effe
