Inter-organellar Communication in Parkinson’s and Alzheimer’s Disease: Looking Beyond Endoplasmic Reticulum-Mitochondria Contact Sites
By onNeurodegenerative diseases (NDs) are generally considered proteinopathies but whereas this may initiate disease in familial cases, onset in sporadic diseases may originate from a gradually disrupted organellar homeostasis. Herein, endolysosomal abnormalities, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and altered lipid metabolism are commonly observed in early preclinical stages of major NDs, including Parkinson's disease (PD) and Alzheimer's disease (AD). Among the multitude of underlying defective molecular mechanisms that have been suggested in the past decades, dysregulation of inter-organellar communication through the so-called membrane contact sites (MCSs) is becoming increasingly apparent. Although MCSs exist between almost every other type of subcellular organelle, to date, most focus has been put on defective communication between the ER and mitochondria in NDs, given these compartments are critical in neuronal survival. Contributions of other MCSs, notably those with endolysosomes and lipid droplets are emerging, supported as well by genetic studies, identifying genes functionally involved in lysosomal homeostasis. In this review, we summarize the molecular identity of the organelle interactome in yeast and mammalian cells, and critically evaluate the evidence supporting the contribution of disturbed MCSs to the general disrupted inter-organellar homeostasis in NDs, taking PD and AD as major examples.
ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling
By onMutations in VPS13C cause early onset, autosomal recessive Parkinson’s Disease (PD). We have established that VPS13C encodes a lipid transfer protein localized to contact sites between the endoplasmic reticulum (ER) and late endosomes/lysosomes. In the current study, we demonstrate that depleting VPS13C in HeLa cells causes an accumulation of lysosomes with an altered lipid profile, including an accumulation of di-22:6-BMP, a biomarker of the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation. In addition, the DNA-sensing cGAS/STING pathway, which was recently implicated in PD pathogenesis, is activated in these cells. This activation results from a combination of elevated mitochondrial DNA in the cytosol and a defect in the degradation of activated STING, a lysosome-dependent process. These results suggest a link between ER-lysosome lipid transfer and innate immune activation and place VPS13C in pathways relevant to PD pathogenesis.
Population fraction of Parkinson’s disease attributable to preventable risk factors
By onParkinson's disease is a fast-growing neurologic disease with no known prevention. Environmental factors like head trauma in sports/combat and pesticide exposure contribute significantly to the disease, suggesting preventable causes for some cases.
Global ubiquitylation analysis of mitochondria in primary neurons identifies endogenous Parkin targets following activation of PINK
By onMuch of the biology surrounding Parkin function has taken place in artificial cell systems. The authors used human neurons to identify and validate 22 protein targets of Parkin, providing a functional Parkin landscape in neuronal cells.
From structure to ætiology: a new window on the biology of leucine-rich repeat kinase 2 and Parkinson’s disease
By onThis review summarizes LRRK2 structure both in a historical and current context, highlighting new insights into the structure of LRRK2 and complexes it forms.
Neuronal Presentation of Antigen and Its Possible Role in Parkinson’s Disease
By onPatients with Parkinson's disease and synucleinopathies show autoimmune features, with T cells recognizing alpha-synuclein. Studies explore T cell-mediated neuronal death in PD and other disorders.
Single-cell spatial transcriptomic and translatomic profiling of dopaminergic neurons in health, aging, and disease
By onThis study used two complementary approaches in a Parkinson's disease mouse model and revealed insights into dopaminergic neuron characteristics, aging markers, and potential disease genes like CASR.
powerEQTL: An R package and shiny application for sample size and power calculation of bulk tissue and single-cell eQTL analysis
By onGenome-wide association studies (GWAS) have revealed thousands of genetic loci for common diseases. One of the main challenges in the post-GWAS era is to understand the causality of the genetic variants. Expression quantitative trait locus (eQTL) analysis has been proven to be an effective way to address this question by examining the relationship between gene expression and genetic variation in a sufficiently powered cohort. However, it is often tricky to determine the sample size at which a variant with a specific allele frequency will be detected to associate with gene expression with sufficient power. This is particularly demanding with single-cell RNAseq studies. Therefore, a user-friendly tool to perform power analysis for eQTL at both bulk tissue and single-cell level will be critical. Here, we presented an R package called powerEQTL with flexible functions to calculate power, minimal sample size, or detectable minor allele frequency in both bulk tissue and single-cell eQTL analysis. A user-friendly, program-free web application is also provided, allowing customers to calculate and visualize the parameters interactively.
Subcellular proteomics of dopamine neurons in the mouse brain
By onUnderstanding the proteome of dopamine neuron is difficult due to the complex cytoarchitecture of the neurons. The authors were able to map the somatodendritic and axonal proteomes of midbrain dopaminergic neurons.
Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease
By onVariants in the GBA1 and LRRK2 genes are the most common genetic risk factors associated with Parkinson disease (PD). Both genes are associated with lysosomal and autophagic pathways, with the GBA1 gene encoding for the lysosomal enzyme, glucocerebrosidase (GCase) and the LRRK2 gene encoding for the leucine-rich repeat kinase 2 enzyme. GBA1-associated PD is characterized by earlier age at onset and more severe non-motor symptoms compared to sporadic PD. Mutations in the GBA1 gene can be stratified into severe, mild and risk variants depending on the clinical presentation of disease. Both a loss- and gain- of function hypothesis has been proposed for GBA1 variants and the functional consequences associated with each variant is often linked to mutation severity. On the other hand, LRRK2-associated PD is similar to sporadic PD, but with a more benign disease course. Mutations in the LRRK2 gene occur in several structural domains and affect phosphorylation of GTPases. Biochemical studies suggest a possible convergence of GBA1 and LRRK2 pathways, with double mutant carriers showing a milder phenotype compared to GBA1-associated PD. This review compares GBA1 and LRRK2-associated PD, and highlights possible genotype-phenotype associations for GBA1 and LRRK2 separately, based on biochemical consequences of single variants.
Transcriptional analysis of peripheral memory T cells reveals Parkinson’s disease-specific gene signatures
By onRecent findings identified PD-associated autoimmune features. Using RNA sequencing, the authors found a broad gene expression profile in memory T cells and a specific PD-associated gene signature.
Genetic and pharmacological reduction of CDK14 mitigates synucleinopathy
By onDecreasing alpha-synuclein levels is a potential therapeutic approach for synucleinopathies. The authors identified CDK14 regulates alpha-synuclein and show reduction of CDK14 reduces alpha-synuclein and PD-like characteristics.
Basal ganglia neurons in healthy and parkinsonian primates generate recurring sequences of spikes
By onBasal ganglia neurons fire in recognizable, repeating sequences of interspike intervals (ISIs), the incidence of which is influenced by the induction of Parkinsonism.
Rodent models based on endolysosomal genes involved in PArkinson’s disease
By onGenes linked to endolysosomal function are connected to Parkinson's disease, suggesting a role in its development. Rodent models targeting these genes like LRRK2 and GBA1 show parkinsonian features, aiding in understanding and treating the disease.
α-Synuclein expression in response to bacterial ligands and metabolites in gut enteroendocrine cells – an in vitro proof of concept study
By onCaudo-rostral migration of pathological forms of α-synuclein from the gut to the brain is proposed as an early feature in Parkinson disease pathogenesis, but the underlying mechanisms remain unknown. Intestinal epithelial enteroendocrine cells sense and respond to numerous luminal signals, including bacterial factors, and transmit this information to the brain via the enteric nervous system and vagus nerve. There is evidence that gut bacteria composition and their metabolites change in Parkinson disease patients and these alterations can trigger α-synuclein pathology in animal models of the disorder. Here we investigated the effect of toll-like receptor and free fatty acid receptor agonists on the intracellular level of α-synuclein and its release using mouse secretin tumour cell line 1 enteroendocrine cells. Secretin tumour cell line 1 enteroendocrine cells were treated for 24 or 48 hours with toll-like receptor agonists (toll-like receptor 4 selective lipopolysaccharide; toll-like receptor 2 selective Pam3CysSerLys4) and the free fatty acid receptor 2/3 agonists butyrate, propionate and acetate. The effect of selective receptor antagonists on the agonists effects after 24 hours was also investigated. The level of α-synuclein protein was measured in cell lysates and cell culture media by western blot and enzyme-linked immunosorbent assay. The level of α-synuclein and tumour necrosis factor messenger RNA was measured by quantitative reverse transcription real time polymerase chain reaction. Stimulation of secretin tumour cell line 1 enteroendocrine cells for 24 and 48 hours with toll-like receptor and free fatty acid receptor agonists significantly increased the amount of intracellular α-synuclein and the release of α-synuclein from the cells into the culture medium. Both effects were significantly reduced by antagonists selective for each receptor. toll-like receptor and free fatty acid receptor agonists also significantly increased tumour necrosis factor transcription and this was effectively inhibited by corresponding antagonists. Elevated intracellular α-synuclein increases the likelihood of aggregation and conversion to toxic forms. Factors derived from bacteria induce α-synuclein accumulation in secretin tumour cell line 1 enteroendocrine cells. Here we provide support for a mechanism by which exposure of enteroendocrine cells to specific bacterial factors found in Parkinson disease gut dysbiosis might facilitate accumulation of α-synuclein pathology in the gut.
α-synuclein promotes neuronal dysfunction and death by disrupting the binding of ankyrin to ß-spectrin
By onα-synuclein plays a key role in the pathogenesis of Parkinson’s disease and related disorders, but critical interacting partners and molecular mechanisms mediating neurotoxicity are incompletely understood. We show that α-synuclein binds directly to ß-spectrin. Using males and females in a Drosophila model of α-synuclein-related disorders we demonstrate that ß-spectrin is critical for α-synuclein neurotoxicity. Further, the ankyrin binding domain of ß-spectrin is required for α-synuclein binding and neurotoxicity. A key plasma membrane target of ankyrin, Na+/K+ ATPase, is mislocalized when human α-synuclein is expressed in Drosophila. Accordingly, membrane potential is depolarized in α-synuclein transgenic fly brains. We examine the same pathway in human neurons and find that Parkinson’s disease patient-derived neurons with a triplication of the α-synuclein locus show disruption of the spectrin cytoskeleton, mislocalization of ankyrin and Na+/K+ ATPase, and membrane potential depolarization. Our findings define a specific molecular mechanism by which elevated levels of α-synuclein in Parkinson’s disease and related α-synucleinopathies leads to neuronal dysfunction and death.
Damaged mitochondria recruit the effector NEMO to activate NF-κB signaling
By onThe connections between molecular mechanisms like mitophagy and tissue-wide features like neuro-inflammation remain unclear. Here, the authors characterize a novel link between these two hallmarks of neurodegeneration.
ATP13A2 Regulates Cellular α-Synuclein Multimerization, Membrane Association, and Externalization
By onATP13A2 loss-of-function mutations are linked to Parkinson’s disease and alpha-synuclein pathology. The authors found that loss of ATP13A2 disrupts lysosomal membrane integrity and causes alpha-synuclein multimerization.
Three-step docking by WIPI2, ATG16L1 and ATG3 delivers LC3 to the phagophore
By onIn this manuscript, in a near-complete pathway from initial membrane recruitment to LC3 lipidation reaction, we show how a three-step targeting mechanism of the ATG12-ATG5-ATG16L1 machinery ensures a high level of regulatory control on autophagy.
Toward a standard model for autophagosome biogenesis
By onHere, we discuss two papers focusing on autophagosome biogenesis in mammals: Olivas et al. confirming ATG9A as an autophagosome component using biochemistry, while Broadbent et al. showing autophagy protein dynamics using particle tracking.
