Chlamydomonas DYX1C1/PF23 is essential for axonemal assembly and proper morphology of inner dynein arms

Cytoplasmic assembly of ciliary dyneins, a process known as preassembly, requires numerous non-dynein proteins, but the identities and functions of these proteins are not fully elucidated. Here, we show that the classical Chlamydomonas motility mutant pf23 is defective in the Chlamydomonas homolog of DYX1C1. The pf23 mutant has a 494 bp deletion in the DYX1C1 gene and expresses a shorter DYX1C1 protein in the cytoplasm. Structural analyses, using cryo-ET, reveal that pf23 axonemes lack most of the inner dynein arms. Spectral counting confirms that DYX1C1 is essential for the assembly of the majority of ciliary inner dynein arms (IDA) as well as a fraction of the outer dynein arms (ODA). A C-terminal truncation of DYX1C1 shows a reduction in a subset of these ciliary IDAs. Sucrose gradients of cytoplasmic extracts show that preassembled ciliary dyneins are reduced compared to wild-type, which suggests an important role in dynein complex stability. The role of PF23/DYX1C1 remains unknown, but we suggest that DYX1C1 could provide a scaffold for macromolecular assembly

The IDA3 adapter, required for intraflagellar transport of I1 dynein, is regulated by ciliary length

Axonemal dyneins, including inner dynein arm I1, assemble in the cytoplasm prior to transport into cilia by intraflagellar transport (IFT). How I1 dynein interacts with IFT is not understood. We take advantage of the Chlamydomonas reinhardtii ida3 mutant, which assembles the inner arm I1 dynein complex in the cytoplasm but fails to transport I1 into the cilium, resulting in I1 dynein-deficient axonemes with abnormal motility. The IDA3 gene encodes an ∼115-kDa coiled-coil protein that primarily enters the cilium during ciliary growth but is not an axonemal protein. During growth, IDA3, along with I1 dynein, is transported by anterograde IFT to the tip of the cilium. At the tip, IDA3 uncouples from IFT and diffuses within the cilium. IFT transport of IDA3 decreases as cilia lengthen and subsides once full length is achieved. IDA3 is the first example of an essential and selective IFT adapter that is regulated by ciliary length. </jats:p

Chlamydomonas DYX1C1/PF23 is essential for axonemal assembly and proper morphology of inner dynein arms

Cytoplasmic assembly of ciliary dyneins, a process known as preassembly, requires numerous non-dynein proteins, but the identities and functions of these proteins are not fully elucidated. Here, we show that the classical Chlamydomonas motility mutant pf23 is defective in the Chlamydomonas homolog of DYX1C1. The pf23 mutant has a 494 bp deletion in the DYX1C1 gene and expresses a shorter DYX1C1 protein in the cytoplasm. Structural analyses, using cryo-ET, reveal that pf23 axonemes lack most of the inner dynein arms. Spectral counting confirms that DYX1C1 is essential for the assembly of the majority of ciliary inner dynein arms (IDA) as well as a fraction of the outer dynein arms (ODA). A C-terminal truncation of DYX1C1 shows a reduction in a subset of these ciliary IDAs. Sucrose gradients of cytoplasmic extracts show that preassembled ciliary dyneins are reduced compared to wild-type, which suggests an important role in dynein complex stability. The role of PF23/DYX1C1 remains unknown, but we suggest that DYX1C1 could provide a scaffold for macromolecular assembly

FAP206 is a Microtubule-Docking Adapter for Ciliary Radial Spoke 2 and Dynein c

Radial spokes are conserved macromolecular complexes that are essential for ciliary motility. A triplet of three radial spokes, RS1, RS2, and RS3, repeats every 96 nm along the doublet microtubules. Each spoke has a distinct base that docks to the doublet and is linked to different inner dynein arms. Little is known about the assembly and functions of individual radial spokes. A knockout of the conserved ciliary protein FAP206 in the ciliate Tetrahymena resulted in slow cell motility. Cryo–electron tomography showed that in the absence of FAP206, the 96-nm repeats lacked RS2 and dynein c. Occasionally, RS2 assembled but lacked both the front prong of its microtubule base and dynein c, whose tail is attached to the front prong. Overexpressed GFP-FAP206 decorated nonciliary microtubules in vivo. Thus FAP206 is likely part of the front prong and docks RS2 and dynein c to the microtubule

Verbal Learning and Memory Deficits across Neurological and Neuropsychiatric Disorders: Insights from an ENIGMA Mega Analysis.

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15–90. The effects of dementia, mild cognitive impairment, Parkinson’s disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia (p \u3c 0.001), while neither depression nor ADHD showed consistent associations with VLM scores (p \u3e 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders

Verbal Learning and Memory Deficits across Neurological and Neuropsychiatric Disorders: Insights from an ENIGMA Mega Analysis.

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15-90. The effects of dementia, mild cognitive impairment, Parkinson's disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia (p 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)