RNA-protein interactions are pivotal in fundamental cellular processes such as translation, mRNA processing, early development, and infection by RNA viruses. However, in

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 P 301 L and V 337 M ) in Caenorhabditis elegans to model tauopathy disorders. Tau pan-neuronal expression caused progressive uncoordinated locomotion (Unc), characteristic of nervous system defects in worms. Subsequently, insoluble tau accumulates and both soluble and insoluble tau is phosphorylated at many of the sites hyperphosphorylated in FTDP-17, AD, and other tauopathies. 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 expressing normal tau. The Unc phenotype is caused by a presynaptic defect. Postsynaptic transmission is intact. This transgenic model will enable mechanistic dissection of tau-induced neurodegeneration and identification of genes and compounds that inhibit pathological tau formation.A bnormally aggregated tau accumulates as neurofibrillary tangles and other lesions in many neurodegenerative diseases including Alzheimer's disease (AD) and frontotemporal dementia with parkinsonism chromosome 17 type (FTDP-17). For AD and most tauopathies, the role tau plays in disease initiation and progression is unknown. However, in FTDP-17, mutations in MAPT, the gene encoding tau, cause the disease (1-3), albeit by incompletely understood mechanisms. One hypothesis is that microtubule (MT)-mediated axonal transport is disrupted, an idea based on the reduced binding affinity of mutant tau for MTs (4). Another hypothesis is that aggregated tau is deleterious to cells, and in FTDP-17, aggregation is driven by either increased free tau concentrations (4) or mutationinduced acceleration of self-aggregation (5, 6). The critical toxic aggregate may be a dimer, a more extensive aggregate, tau filaments, or the end-stage tangles. The phosphorylation state of tau may also be important, as pathologic insoluble tau is hyperphosphorylated (7).To identify critical steps in tau-induced neurodegeneration, we generated a MAPT transgenic (Tg) Caenorhabditis elegans model of FTDP-17. Pan-neuronal expression of normal or FTDP-17 mutant MAPT resulted in altered behavior (uncoordinated movement), accumulation of insoluble phosphorylated tau, age-dependent loss of axons and neurons, and s...

Abnormal TDP-43 aggregation is a prominent feature in the neuropathology of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. Mutations in TARDBP, the gene encoding TDP-43, cause some cases of ALS. The normal function of TDP-43 remains incompletely understood. To better understand TDP-43 biology, we generated mutant mice carrying a genetrap disruption of Tardbp. Mice homozygous for loss of TDP-43 are not viable. TDP-43 deficient embryos die about day 7.5 of embryonic development thereby demonstrating that TDP-43 protein is essential