Spatial transcriptomics reveals molecular dysfunction associated with Lewy pathology
By onThe results identify neurons vulnerable to Lewy pathology in the PD cortex and identify a conserved signature of molecular dysfunction in both mice and humans.
Structural basis for membrane recruitment of ATG16L1 by WIPI2 in Autophagy
By onThe authors showed through structural determination how ATG16L1 and WIPI2 interact and compared the other WIPI proteins showing the variety of mechanisms of membrane recruitment by WIPI proteins.
Association between the LRP1B and APOE loci and the development of Parkinson’s disease dementia
By onGenetic analysis of 3,964 PD cases revealed APOE-ϵ4 allele and new loci as risk factors for PD dementia progression, implicating amyloid pathway in PDD development and potential for amyloid-targeting therapy.
Brain Repair by Cell Replacement via In Situ Neuronal Reprogramming
By onNeurodegenerative diseases, characterized by progressive neural loss, have been some of the most challenging medical problems in aging societies. Treatment strategies such as symptom management have little impact on disease progression, while intervention with specific disease mechanisms may only slow down disease progression. One therapeutic strategy that has the potential to reverse the disease phenotype is to replenish neurons and rebuild the pathway lost to degeneration. Although it is generally believed that the central nervous system has lost the capability to regenerate, increasing evidence indicates that the brain is more plastic than previously thought, containing perhaps the biggest repertoire of cells with latent neurogenic programs in the body. This review focuses on key advances in generating new neurons through in situ neuronal reprogramming, which is tied to fundamental questions regarding adult neurogenesis, cell source, and mechanisms for neuronal reprogramming, as well as the ability of new neurons to integrate into the existing circuitry.
Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex
By onAuthors determine cryo-EM structure of human ULK1C core and its complex with PI3KC3-C1. ULK1C core undergoes a rearrangement from 2:1:1 to 2:2:2 stoichiometry, suggesting a structural mechanism for autophagy initiation.
The Hsc70 disaggregation machinery removes monomer units directly from α-synuclein fibril ends
By onUsing microfluidic diffusional sizing, the authors show that the molecular chaperone family Hsp70 (specifically Hsc70, DnaJB, and Apg2) can completely dissolve alpha-synuclein aggregation and revert it back to its monomeric state.
Phenotypic effect of GBA1 variants in individuals with and without Parkinson disease: the RAPSODI study
By onThe authors’ results support previous evidence that GBA1-positive PD has a specific phenotype with more severe non-motor symptoms. The authors did not reproduce previous findings of more frequent prodromal PD signs in non-affected GBA1 carriers.
A feed-forward pathway drives LRRK2 kinase membrane recruitment and activation
By onLRRK2 interacts with Rab8A and Rab10 at specific binding sites, enhancing LRRK2 kinase activity on membranes. This feed-forward pathway regulates LRRK2 activation and substrate phosphorylation.
Multiscale model of primary motor cortex circuits predicts in vivo cell type-specific, behavioral state-dependent dynamics
By onA detailed multiscale model of mouse primary motor cortex accurately predicted responses to behavioral states and manipulations, aiding in understanding cortical function at different scales.
Spatial snapshots of amyloid precursor protein intramembrane processing via early endosome proteomics
By onThe authors developed an assay, Endo-IP, to rapidly isolate early and sorting endosomes. Using this method, they found a unique proteomic landscape of early/sorting endosomes, distinct from lysosomal proteomic landscape.
Inhibition of striatal dopamine release by the L-type calcium channel inhibitor isradipine co-varies with risk factors for Parkinson’s
By onThis data show that LTCC function in DA axons, and isradipine effect, are locally governed and suggest they vary in a manner that in turn might impact on, or reflect, the cellular stress that leads to parkinsonian degeneration.
Metagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms
By onA study on Parkinson's disease links gut microbiome to brain health. Analysis of 490 PD patients and 234 controls reveals dysbiosis, microbial clusters, and disease-promoting factors in PD microbiome, offering insights for future research.
Protein network analysis links the NSL complex to Parkinson’s disease via mitochondrial and nuclear biology
By onA bioinformatics approach was taken to investigate the proteome of the NSL complex, to unpick its relevance to PD progression. The authors’ data points to NSL complex members OGT and WDR5 as key drivers of this increased PD association.
In situ architecture of neuronal α-Synuclein inclusions
By onAlpha-synuclein aggregation has been associated with Parkinson’s disease. Using cutting-edge imaging tools, the authors show neuronal alpha-synuclein inclusions within their native states.
The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model
By onTau neuronal aggregation is a driver of some neurodegenerative disorders. The authors show that a protein,Clusterin, delays Tau aggregation and suppresses seeding activity.
A Markov random field model-based approach for differentially expressed gene detection from single-cell RNA-seq data
By onSingle-cell RNA-sequencing technology enables the identification of cell-type-specific differential gene expressions. MARBLES, a new statistical model, effectively detects DE genes across conditions.
A possible role for VPS13-family proteins in bulk lipid transfer, membrane expansion and organelle biogenesis
By onAt organelle–organelle contact sites, proteins have long been known to facilitate the rapid movement of lipids. Classically, this lipid transport involves the extraction of single lipids into a hydrophobic pocket on a lipid transport protein. Recently, a new class of lipid transporter has been described with physical characteristics that suggest these proteins are likely to function differently. They possess long hydrophobic tracts that can bind many lipids at once and physically span the entire gulf between membranes at contact sites, suggesting that they may act as bridges to facilitate bulk lipid flow. Here, we review what has been learned regarding the structure and function of this class of lipid transporters, whose best characterized members are VPS13 and ATG2 proteins, and their apparent coordination with other lipid-mobilizing proteins on organelle membranes. We also discuss the prevailing hypothesis in the field, that this type of lipid transport may facilitate membrane expansion through the bulk delivery of lipids, as well as other emerging hypotheses and questions surrounding these novel lipid transport proteins.
Endosomal escape of RNA therapeutics: How do we solve this rate-limiting problem?
By onWith over 15 FDA approved drugs on the market and numerous ongoing clinical trials, RNA therapeutics, such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs), have shown great potential to treat human disease. Their mechanism of action is based entirely on the sequence of validated disease-causing genes without the prerequisite knowledge of protein structure, activity or cellular location. In contrast to small molecule therapeutics that passively diffuse across the cell membrane's lipid bilayer, RNA therapeutics are too large, too charged, and/or too hydrophilic to passively diffuse across the cellular membrane and instead are taken up into cells by endocytosis. However, endosomes are also composed of a lipid bilayer barrier that results in endosomal capture and retention of 99% of RNA therapeutics with 1% or less entering the cytoplasm. Although this very low level of endosomal escape has proven sufficient for liver and some CNS disorders, it is insufficient for the vast majority of extra-hepatic diseases. Unfortunately, there are currently no acceptable solutions to the endosomal escape problem. Consequently, before RNA therapeutics can be used to treat widespread human disease, the rate-limiting delivery problem of endosomal escape must be solved in a nontoxic manner.
Peripheral neuronal activation shapes the microbiome and alters gut physiology
By onThe authors specifically activate ChAT- or TH-expressing gut-associated neurons in mice and perform multi-omics, finding that subsets of peripherally-activated neurons differentially regulate the gut microbiome and host GI physiology.
A step forward for LRRK2 inhibitors in Parkinson’s disease
By onIn common with the majority of neurodegenerative diseases, there is an urgent and pressing need for novel disease modifying therapies for Parkinson’s disease (PD). Reporting the results of the first human trial for kinase inhibitors of Leucine Rich Repeat Kinase 2 (LRRK2), Jennings and co-workers presented an important advance along the drug development pathway for a target that has long been a priority for the Parkinson’s research community. The focus discusses several topics including: functional characterisation of LRRK2 and the impact of mutations and a key role for altered kinase function in disease; the human genetics of the LRRK2 locus; the outcome of a first-in-human clinical trial for LRRK2 kinase inhibitors by Denali therapeutics, LRRK2 kinase inhibition as a therapeutic strategy in humans; the strategy of using antisense oligonucleotide knockdown approach and the challenges faced by clinical trials – measuring outcomes in chronic, slowly progressing disorders with variable rates of progression.
