Mutations in GPNMB associated with Amyloid cutis dyschromica alter intracellular trafficking and processing of GPNMB
By onThis 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.
Systemic inflammation triggers long-lasting neuroinflammation and accelerates neurodegeneration in a rat model of Parkinson’s disease overexpressing human alpha-synuclein
By onIn the present study, the authors assessed the development of PD-like symptoms on a PD rat model overexpressing human α-synuclein at a presymptomatic age, exposed to a pro-inflammatory insult by injection of lipopolysaccharide.
Alpha-synuclein overexpression can drive microbiome dysbiosis in mice
By onPersons with PD have a unique gut microbe composition. Studies on human and rodent microbiomes before and during the disease are lacking. α-syn overexpression in mice alters gut microbiome with age, potentially impacting disease progression.
Polyglucosan body density in the aged mouse hippocampus is controlled by a novel modifier locus on chromosome 1
By onAging can be associated with the accumulation of polyglucosan bodies (PGBs).Here, the authors investigated the genetic basis and functional impact of age-related PGB accumulation in mice.
iSCORE-PD: an isogenic stem cell collection to research Parkinson Disease
By onA collection of 55 cell lines genetically engineered to harbor mutations in genes associated with monogenic PD were generated using CRISPR/Cas9 and prime editing. This collection offers a valuable platform for studying Parkinson's disease.
Large-scale visualisation of α-synuclein oligomers in Parkinson’s disease brain tissue
By onASA-PD (Advanced Sensing of Aggregates - PD) is a new imaging method to map α-synuclein oligomers in human brain tissue, revealing specific early proteinopathy markers in PD patients. This may aid in understanding disease mechanisms.
Modeling gene-environment interactions in Parkinson’s Disease: Helicobacter pylori infection of Pink1-/- mice induces CD8 T cell-dependent motor and cognitive dysfunction.
By onHere, we demonstrate in a mouse model deficient in the PD-associated gene Pink, that infection with the human PD-associated gastric bacterium Helicobacter pylori leads to development of motor and cognitive signs resembling prodromal features of PD.
Alpha-synuclein aggregates trigger anti-viral immune pathways and RNA editing in human astrocytes
By onPD involves proteinopathy and astrogliosis. Oligomeric alpha-synuclein induces astrocyte inflammation, leading to neuronal toxicity. ADAR1-mediated RNA editing plays a role in sustaining inflammatory states, potentially driving PD neuroinflammation.
GLP-1 receptor agonism ameliorates Parkinson’s disease through 1 modulation of neuronal insulin signalling and glial suppression
By onGLP-1 agonism reverses this resistance, reducing oxidative stress, improving cellular function, and enhancing neuronal viability. Exenatide treatment shows promise in clinical trials as a disease modifying strategy for synucleinopathies.
Adoptive transfer of mitochondrial antigen-specific CD8+ T-cells in mice causes parkinsonism and compromises the dopamine system
By onBy adoptively transferring mitochondrial peptide-specific CD8+ T cells into WT and PINK1 KO mice, we find that this leads to L-DOPA-reversible motor impairment and to robust loss of DA neurons and axonal markers in the striatum in both PINK KO and WT
LRRK2 G2019S mutation suppresses differentiation of Th9 and Treg cells via JAK/STAT3
By onThe Leucine-rich repeat kinase-2 (LRRK2) G2019S mutation, resulting in aberrantly enhanced kinase activity, is one of the well-recognized genetic risk factors in Parkinson's Disease (PD). Increased LRRK2 activity was also observed in immune cells from PD patients. Emerging results have also unveiled an upsurge in alpha-synuclein (alpha-syn)-specific CD4+ T cell responses in PD patients. Given that LRRK2 mutations in PD are germline mutations, there are unmet meets to explore whether LRRK2 G2019S mutation contributes to the pathogenesis of PD via altering CD4+ T-cell functions. To fill this knowledge gap, we generated a new T cell receptor (TCR) transgenic mouse strain bearing LRRK2 G2019S knock-in mutation, OT-II/LRRK2 (Refer to Mut). As CD4+ T cells from OT-II mice specifically recognize ovalbumin, this new strain enables us to explore the impact of LRRK2 G2019S mutation on T-cell functions in an antigen-specific manner. We found that the abundance and proliferation of major immune subsets in spleen tissue from Mut mice are comparable to wild-type (OT-II, Refer to WT) control. However, when we characterized T cell differentiation in these two strains, T cells derived from Mut mice displayed increased Th2 differentiation (IL-4) and decreased Th9 (IL-9) and Treg (Foxp3+ %) differentiation. LRRK2 G2019S mutation significantly altered the expression levels of master transcription factors (TFs) for T cell differentiation. Specifically, Mut T cells displayed an increase in mRNA expression of Gata3 (TF for Th2), a decrease in expression of Irf4 and Foxp3 (TFs for Th9 and Treg, respectively). Mechanistically, LRRK2 mutation decreased IL-9 production and Treg cell population through the JAK/STAT3 signaling. In conclusion, LRRK2 plays a critical role in regulating T cell differentiation, warranting further studies to evaluate the impacts of altered T cell differentiation led by LRRK2 mutation in dopaminergic neuron damages.
Deep sequencing of proteotoxicity modifier genes uncovers a Presenilin-2/beta-amyloid-actin genetic risk module shared among alpha-synucleinopathies
By onThe authors study patients based on protein aggregation phenotype to detect variants in a targeted set of genes.
A proteome-wide quantitative platform for nanoscale spatially resolved extraction of membrane proteins into native nanodiscs
By onThe intricate molecular environment of the native membrane profoundly influences every aspect of membrane protein (MP) biology. Despite this, the most prevalent method of studying MPs uses detergent- like molecules that disrupt and remove this vital local membrane context. This severely impedes our ability to quantitatively decipher the local molecular context and comprehend its regulatory role in the structure, function, and biogenesis of MPs. Using a library of membrane-active polymers we have developed a platform for the high-throughput analysis of the membrane proteome. The platform enables near-complete spatially resolved extraction of target MPs directly from their endogenous membranes into native nanodiscs that maintain the local membrane context. We accompany this advancement with an open-access quantitative database that provides the most efficient extraction conditions of 2065 unique mammalian MPs. Our method enables rapid and near-complete extraction and purification of target MPs directly from their endogenous organellar membranes at physiological expression levels while maintaining the nanoscale local membrane environment. Going beyond the plasma membrane proteome, our platform enables extraction from any target organellar membrane including the endoplasmic reticulum, mitochondria, lysosome, Golgi, and even transient organelles such as the autophagosome. To further validate this platform we took several independent MPs and demonstrated how our resource can enable rapid extraction and purification of target MPs from different organellar membranes with high efficiency and purity. Further, taking two synaptic vesicle MPs, we show how the database can be extended to capture multiprotein complexes between overexpressed MPs. We expect these publicly available resources to empower researchers across disciplines to capture membrane ‘nano-scoops’ containing a target MP efficiently and interface with structural, functional, and other bioanalytical approaches. We demonstrate an example of this by combining our extraction platform with single-molecule TIRF imaging to demonstrate how it can enable rapid determination of homo-oligomeric states of target MPs in native cell membranes.
Comparative study of enriched dopaminergic neurons from siblings with Gaucher disease discordant for parkinsonism
By onComparative studies of dopaminergic neurons differentiated from iPSCs derived from siblings with Gaucher disease discordant for parkinsonism provide an avenue to explore genetic modifiers contributing to GBA1-associated parkinsonism.
Comparison of Alternative pre-mRNA Splicing and Gene Expression Patterns in Midbrain Lineage Cells Carrying Familial Parkinson’s Disease Mutations
By onGenome editing was used to introduce PD mutations into stem cells, differentiating them into midbrain cells. Analysis revealed that PD mutations cause significant pre-mRNA splicing changes, which could serve as biomarkers for familial PD.
Reward perseveration is shaped by GABAA-mediated dopamine pauses
By onThis study employs a novel drug targeting technology DART(drug acutely restricted by tethering), to selectively block GABAA receptors on VTADA neurons as mice engage in Pavlovian learning.
Inhibition of Indirect Pathway Activity Causes Abnormal Decision-Making In a Mouse Model of Impulse Control Disorder in Parkinson’s Disease
By onHealthy action selection relies on the coordinated activity of striatal direct and indirect pathway neurons. In Parkinson’s disease (PD), in which loss of midbrain dopamine neurons is associated with progressive motor and cognitive deficits, this coordination is disrupted. Dopamine replacement therapy can remediate motor symptoms, but can also cause impulse control disorder (ICD), which is characterized by pathological gambling, hypersexuality, and/or compulsive shopping. The cellular and circuit mechanisms of ICD remain unknown. Here we developed a mouse model of PD/ICD, in which ICD-like behavior was assayed with a delay discounting task. We found that in parkinsonian mice, the dopamine agonist pramipexole drove more pronounced delay discounting, as well as disrupted firing in both direct and indirect pathway neurons. We found that chemogenetic inhibition of indirect pathway neurons in parkinsonian mice drove similar phenotypes. Together, these findings provide a new mouse model and insights into ICD pathophysiology.
Chronic hyperactivation of midbrain dopamine neurons causes preferential dopamine neuron degeneration
By onParkinson’s disease is linked to substantia nigra dopamine neuron death. To determine if chronic changes in activity of these neurons plays a role, the authors created a mouse model. This resulted in altered motor activity and selective neuron loss.
3D imaging of neuronal inclusions and protein aggregates in human neurodegeneration by multiscale X-ray phase-contrast tomography
By onThis study leverages X-ray phase-contrast tomography for detailed analysis of neurodegenerative diseases focusing on the 3D visualization and quantification of neuropathological features within fixed human postmortem tissue.
Genetic screening and metabolomics identify glial adenosine metabolism as a therapeutic target in Parkinson’s disease
By onA Drosophila model identified glial-based therapeutic targets for PD, focusing on adenosine metabolism genes. Knocking down Ak1 improved symptoms and increased adenosine levels, suggesting adenosine as a potential therapeutic target for PD.
