Kraemer BC et al. (2007) Hum Mol Genet "SUT-1 enables tau-induced neurotoxicity in C. elegans."

Schellenberg GD, Kraemer BC

[Hum Mol Genet, 2007]

We previously reported a transgenic C. elegans model for tauopathies in which expression of human tau in neurons caused insoluble phosphorylated tau accumulation, neurodegeneration, and uncoordinated movement (Unc). To identify genes participating in tau neurotoxicity, we conducted a forward genetic screen for mutations that ameliorate tau-induced uncoordination. The recessive mutation sut-1(bk79) partially suppresses the Unc phenotype, tau aggregation, and neurodegenerative changes caused by tau. We identified the sut-1 gene and found it encodes a novel protein. We conducted a yeast two hybrid screen to identify SUT-1 binding partners and found UNC-34, the C. elegans homolog of the cytoskeletal regulatory protein Enabled (ENA). In vitro protein binding assays and genetic studies validated the interaction between SUT-1 and UNC-34. The SUT-1/UNC-34 protein-protein interaction plays a role in both the normal function of UNC-34 and in the tauinduced phenotype. Thus, we have found a conserved molecular pathway participating in tau neurotoxicity in C. elegans.

Kraemer BC et al. (2006) Hum Mol Genet "Molecular pathways that influence human tau-induced pathology in Caenorhabditis elegans."

Kraemer BC, Burgess JK, Chen JH, Thomas JH, Schellenberg GD

[Hum Mol Genet, 2006]

Mutations in the gene encoding tau cause frontotemporal dementia with parkinsonism - chromosome 17 type (FTDP-17). In FTDP-17, Alzheimer''s disease (AD), and other tauopathies, aggregated hyper-phosphorylated tau forms the neurofibrillary tangles characteristic of these disorders. We previously reported a C. elegans model for tauopathies using human normal and FTDP-17 mutant tau as transgenes. Neuronal transgene expression caused insoluble phosphorylated tau accumulation, neurodegeneration, and uncoordinated (Unc) movement. Here we describe a genome-wide RNA mediated interference (RNAi) screen for genes that modify the tau induced Unc phenotype. We tested RNAi sequences for 16,757 genes and found 75 that enhanced the transgene induced Unc phenotype. Forty-six of these genes have sequence similarity to known human genes and fall into a number of broad classes including kinases, chaperones, proteases, and phosphatases. The remaining 29 modifiers have sequence similarity only with other nematode genes. To determine if the enhancers are specific for the tau-induced Unc behavior, we exposed several non-tau Unc mutants to tau RNAi enhancer clones. Fifteen enhancers modified phenotypes in multiple Unc mutants, while 60 modified only the Unc phenotype in the tau transgenic lines. We also introduced the tau transgene into the background of genetic loss of function mutations for a subset of the enhancer genes. Tau transgenic animals homozygous for loss of these enhancer genes exhibited increased impaired motility relative to the tau transgene line alone. This work uncovers novel candidate genes that prevent tau toxicity, as well as genes previously implicated in tau-mediated neurodegeneration.

Kraemer BC et al. (2003) Proc Natl Acad Sci U S A "Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy."

Zhang B, Schellenberg GD, Trojanowski JQ, Thomas JH, Leverenz JB, Kraemer BC

[Proc Natl Acad Sci U S A, 2003]

Frontotemporal dementia with parkinsonism chromosome 17 type (FTDP-17) is caused by mutations in MAPT, the gene encoding tau. FTDP-17 begins with executive function deficits and other abnormal behaviors, which progress to dementia. Neurodegenerative changes include accumulation of aggregated tau as neuronal and glial fibrillary tangles. Aggregated tau is seen in numerous other neurodegenerative diseases, including Alzheimer's disease (AD). We expressed normal and FTDP-17 mutant human tau (mutations p301L and V337M) in Caenorhabditis elegans to model taupathy disorders. Tau pan-neuronal expression caused progressive uncoordinated locomotion (Unc), characteristic of nervous system defects in worms. Subsequently, insoluble tau accumulates and both hyperphosphorylated in FTDP-17, AD, and other taupathies. Substantial neurodegeneration, seen as bulges and gaps in nerve cords followed by loss of neurons, occurs after insoluble tau begins to accumulate. Axons show vacuoles, membranous infoldings, and whorls with associated amorphous tau accumulations and abnormal tau-positive aggregates. FTDP-17 mutation lines had a more severe Unc phenotype, accumulated more insoluble tau at a younger age, were more resistant to cholinergic inhibitors, and had more severe axonal degeneration when compared with lines of expressing normal tau. The Unc phenotype is caused by a presynaptic defect. Postsynaptic transmission is intact. This transgenic model will enable mechanistic dissection of genes and compounds that inhibit pathological

Currey, Heather N et al. (2020) MicroPubl Biol

Liachko, Nicole F, Currey, Heather N, Malinkevich, Anna, Melquist, Penny

[MicroPubl Biol, 2020]

Aggregates of the protein tau are the hallmark of several neurodegenerative diseases including Alzheimers disease, frontotemporal lobar degeneration (FTLD-tau), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Picks disease, and chronic traumatic encephalopathy (CTE) (VandeVrede, Boxer et al. 2020). Mutations in the gene coding for tau, MAPT, can cause FTLD-tau, directly linking tau dysfunction with disease (Dickson, Kouri et al. 2011). Another protein, TDP-43, comprises aggregates which are the primary hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), and mutations in the gene coding for TDP-43, TARDBP, can cause disease (Kawakami, Arai et al. 2019). To model tau or TDP-43 proteinopathies, transgenic C. elegans have been generated that express the full-length human protein pan-neuronally. These worms exhibit significant uncoordinated movement on plates and impaired thrashing in liquid (Kraemer, Zhang et al. 2003; Liachko, Guthrie et al. 2010). However, tau- and TDP-43- expressing worms are not paralyzed; they still move their heads and have some motility on the plate (coiling, crawling with tail-drag, head swinging) which are not captured in standard crawling or thrashing assays. To assay differences in total activity, we used a WMicroTracker ARENA System (Phylumtech, AR and InVivo Biosystems, USA). The ARENA captures population level activity data by relying on optical interferometry, which uses a large array of infrared LED microbeams to detect both the movement and position of worms on a culture plate. Disruption of an LED microbeam by worm movement is recorded by repeat scans of the 6-well culture plate, and allows for real-time processing. The software identifies changes in the location of disrupted beams between scans and assigns an activity score based on differences identified between each consecutive scan (Simonetta SH). Both tau- and TDP-43- expressing worms had significantly less activity per minute than N2 (Figure 1). Further, we found the ARENA- assessed activity data recapitulated the relative severity of phenotypes among the strains as measured by motility assays. For example, both CK10 (tau V337M) and CK144 (tau WT) have significantly uncoordinated movement when crawling or thrashing in liquid, with CK144 having worse motility than CK10, due to its much higher burden of total tau protein expressed (Kraemer, Zhang et al. 2003). Likewise, CK410 (TDP-43 WT) worms have slightly impaired motility compared with N2 when crawling on a plate, CK423 (TDP-43 M337V) are severely uncoordinated, and CK426 (TDP-43 A315T) have the most severe uncoordinated phenotype. The relative toxicities of these strains stem from the effects of the mutations, as TDP-43 protein expression is relatively even among these transgenic strains (Liachko, Guthrie et al. 2010). Interestingly, the ARENA captures activity of these severely uncoordinated worms that move poorly in motility assays such as crawling on an NGM plate or thrashing in liquid (Kraemer, Zhang et al. 2003; Liachko, Guthrie et al. 2010). Therefore, ARENA assessment of aggregate activity may be a more accurate metric for capturing non-locomotor movement of C. elegans that are severely uncoordinated.