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Aaron Gitler, Robert Farese Jr. and colleagues identify the RNA lariat debranching enzyme Dbr1 as a potent suppressor of TDP-43 toxicity in yeast. They further show that Dbr1 knockdown reduces TDP-43 toxicity in mammalian cells, identifying this enzyme as a possible therapeutic target in amyotrophic lateral sclerosis and other diseases marked by TDP-43 accumulation.

Ernest Fraenkel and colleagues present ResponseNet, a method used to integrate analysis of genetic and transcriptional datasets, and its application characterizing yeast cellular responses to alpha-synuclein toxicity.

Astrocyte activation may contribute to neurodegenerative disease. Here the authors show that the combined knockout of three factors known to promote astrogliosis, IL-1α, TNFα and C1qa, leads to improved survival in the SOD1^G93A mouse model of ALS.

The causes of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) are poorly understood, although the protein TDP-43 seems to be involved. These authors show that the polyglutamine-containing protein ataxin 2 interacts with TDP-43 and is a potent modifier of TDP-43 toxicity. Moreover, intermediate-length polyglutamine expansions in the ataxin 2 gene significantly associate with ALS. These data establish the ataxin 2 gene as a new and relatively common ALS disease susceptibility gene.

Susan Lindquist and colleagues report a genetic interaction between α-synuclein and the ortholog of human ATP13A2 (PARK9) in yeast, two genes that when mutated cause Parkinson's disease. They further show that yeast PARK9 protects cells from manganese toxicity, a known environmental risk factor for Parkinson's disease.

A mutation in the C9orf72 gene is the most common genetic cause of two neurodegenerative diseases. A newly identified immunological function for the C9orf72 protein points to a potential therapeutic strategy for these diseases.

Protein aggregation is a characteristic of several neurodegenerative diseases. But disease-associated aggregates of the protein TDP-43 have now been shown to have a beneficial role in healthy muscle.

TDP-43 controls an exon splicing event in UNC13A that results in the inclusion of a cryptic exon associated with frontotemporal dementia and amyotrophic lateral sclerosis.

Biologist who found unexpected power in protein folding.

Genome-wide approaches are used to discover the RNA-binding targets of the amyotrophic lateral sclerosis (ALS) disease protein FUS/TLS. These studies reveal some shared targets with another ALS-linked RNA-binding protein, TDP-43, suggesting common pathogenic mechanisms.

“Intracellular phase separation is emerging as a universal principle for organizing biochemical reactions in time and space. Here the authors show that PopZ condensate dynamics support cell division and using PopZ modular architecture, the tunable PopTag platform was developed to enable designer condensates.”

Reduced abundance of immune-stimulating gut bacteria ameliorated the inflammatory and autoimmune phenotypes of mice with mutations in C9orf72, which in the human orthologue are linked to amyotrophic lateral sclerosis and frontotemporal dementia.

Ian Blair and colleagues use genome-wide linkage analysis and whole exome sequencing to identify mutations in the CCNF gene in large cohorts of amyotrophic lateral sclerosis and frontotemporal dementia patients. In addition to validating the mutations in international cohorts, the authors also show that mutant CCNFgene product affects ubiquitination and protein degradation in cultured cells.

Astrocytes can respond to diseases and injuries of the central nervous system by driving the death of neurons and mature oligodendrocytes through the delivery of long-chain saturated fatty acids contained in lipoparticles.

The (G4C2)₃₀₊ repeat expansion is the most prominent mutation in familial FTD and ALS. Here the PAF1 complex is identified as a transcriptional regulator of this unique mutation. Data from FTD tissue positive for the C9orf72 mutation support the relevance of this complex in disease.

The identification of pathogenic mutations within prion-like domains (PrLDs) of the RNA-binding proteins hnRNPA2B1 and hnRNPA1 add to our understanding of how mutations in these proteins lead to degenerative disease, and highlight the potential importance of PrLDs in degenerative diseases of the nervous system, muscle and bone.

Exome sequencing of 47 ALS trios (patients and their unaffected parents) identified de novo mutations, including a mutation in the neuronal chromatin remodeling complex component, SS18L1. SS18L1 interacted with the ALS protein FUS, and mutation of SS18L1 in primary neurons resulted in impaired neurite outgrowth.

A genome-wide CRISPR screen for suppressors and enhancers of C9ORF72 dipeptide-repeat protein toxicity identifies candidate genes involved in nucleocytoplasmic transport and other pathways including RNA processing and chromatin modification.

Nancy Bonini and colleagues performed a genome-wide yeast screen for modifiers of TDP-43 toxicity and identified genes in RNA metabolism, including several RNA-binding proteins with connections to stress granules. They determined that therapeutic modulation of stress granule–associated eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models in flies and primary mammalian neurons.

Cytoplasmic, amyloid-like oligomeric assemblies that contain TDP-43 are increased in damaged tissues with elevated regeneration, thereby enhancing the possibility of amyloid fibre formation and/or aggregation of TDP-43 in disease.

A nucleotide repeat expansion in the C9orf72 gene is the most common cause of amyotrophic lateral sclerosis. The mutation causes production of aberrant proteins by an enigmatic form of translation. Yamada et al. identify that RPS25 is required for this form of translation.

Blum et al. performed single-nucleus RNA sequencing of the adult mouse spinal cord. This analysis revealed heterogeneity in the autonomic and skeletal motor systems and provides a resource to study motor neurons in health and disease.

ALS/FTD-related C9orf72 dipeptide-repeat proteins inhibit protein translation and impair stress granule dynamics, and they cause motor and cognitive deficits in mice.

A decrease in ataxin-2 levels leads to a reduction in the aggregation of TDP-43, markedly increased lifespan and improved motor function in a transgenic mouse model of TDP-43 proteinopathy.

C9orf72 mutations are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. With unbiased screens in Saccharomyces cerevisiae, Jovicic et al. identified potent modifiers of toxicity of dipeptide repeat proteins produced by unconventional translation of the C9orf72 repeat expansions, pointing to nucleocytoplasmic transport impairments as potential disease mechanisms.

A nucleotide repeat expansion (NRE) within the chromosome 9 open reading frame 72 (C9orf72) gene is linked to multiple neurological conditions. Rothstein and colleagues evaluate the evidence indicating that the NRE causes a loss of C9orf72 function or drives toxic gain-of-function mechanisms and consider the cellular defects through which the mutation drives disease pathology.