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Principal Investigator: Rebecca Liang Kow
Organization: SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
Fiscal Year: 2024
Award: $623,631
Funding agency: National Institute on Aging
Background: Alzheimer’s disease and other neurodegenerative diseases with accumulation of pathological
tau protein, termed tauopathies, are increasing in prevalence and burden to the US population. However, there
are still no therapies to cure or reverse tauopathies. Despite strong evidence that pathological tau causes
neurodegeneration and the development of numerous models of tau toxicity, the molecular mechanisms
underlying the toxicity induced by pathological tau are still incompletely understood. To discover novel genetic
suppressors of tau toxicity, forward genetic screening was performed in a Caenorhabditis elegans model of
tauopathy. A W292X mutation in SUT-6 (NIPP1 in mammals) was recently identified as a novel modulator of
tauopathy. SUT-6/NIPP1 is a multifunctional, multidomain protein that regulates phosphatase activity, splicing
of mRNAs, and gene transcription. The W292X mutant of SUT-6 removes the last 11 amino acids off the C-
terminus of SUT-6 and shows strong, dominant and cell-autonomous suppression of tau-induced toxicity while
loss of SUT-6 expression shows weaker suppression of tau-induced toxicity. This suggests that altering SUT-
6/NIPP1 interactions with protein partners that regulate phosphatase, splicing, or other activities leads to
suppression of tau toxicity.
Hypothesis: SUT-6/NIPP1 modulates tau toxicity by altering protein phosphatase 1 and/or splicing activity in
translationally conserved mechanisms of disease.
Proposal Aims: The specific aims of this project are: 1) Define the functions of SUT-6/NIPP1 important for
suppressing tau toxicity by introducing mutations into the sut-6 gene and evaluating the effects in a C. elegans
model of tau pathology. 2) Determine downstream mediators of SUT-6/NIPP1’s suppression of tau toxicity by
identifying neuronal interactors of SUT-6 and NIPP1 and performing epistasis analysis of identified interactors
in a C. elegans model of tau pathology. 3) Examine the translational impact of NIPP1 modulation on tauopathy
using a mouse model of tau pathology.
Expected Outcomes: The proposed studies will deepen our understanding of a novel, translationally relevant
mechanism for regulating tauopathy and our overall knowledge of the mechanisms of tau-induced toxicity,
pathology and disease generally. This knowledge will lead to better therapeutic strategies targeting tau in
Alzheimer’s disease and other tauopathies.
Terms: <AD dementia><AD related dementia><ADRD><ATP-protein phosphotransferase><Alleles><Allelomorphs><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's and related dementias><Alzheimer's brain><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease brain><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease related dementia><Alzheimers Dementia><Amentia><Amino Acids><Animal Model><Animal Models and Related Studies><Behavioral><Binding><C elegans><C-terminal><C. elegans><C.elegans><Caenorhabditis elegans><Cause of Death><Cell Body><Cell model><Cells><Cellular model><Clinical><Degenerative Neurologic Disorders><Dementia><Development><Disease><Disorder><ENX-1><EZH1><EZH2><EZH2 gene><Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit><Epistasis><Epistatic Deviation><FHA Domain><Forkhead-Associated Domain><Frontal Temporal Dementia><Frontotemporal Dementia><Gene Transcription><GeneHomolog><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Epistasis><Genetic Screening><Genetic Transcription><Genetic analyses><Genetic defect><Goals><Healthcare><Homolog><Homologous Gene><Homologue><Human><Interaction Deviation><KMT6><KMT6A><Kinase Family Gene><Knowledge><MT-bound tau><Mammalia><Mammals><Mediating><Mediator><Memory Deficit><Memory impairment><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Mutation><N-terminal><NH2-terminal><NIPP-1><NIPP1 protein><Names><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuron Degeneration><Neuronal Dysfunction><Neurons><Nuclear><Outcome><Pathologic><Pathology><Peptide Domain><Phenotype><Phosphatases><Phosphohydrolases><Phosphomonoesterases><Phosphoprotein Phosphatase><Phosphoprotein Phosphatase-2C><Phosphoprotein Phosphohydrolase><Phosphoric Monoester Hydrolases><Population><Prevalence><Primary Senile Degenerative Dementia><Protein Domains><Protein Kinase><Protein Phosphatase C><Protein Phosphatase Gene><Protein Phosphatase-1><Protein Phosphatase-2A><Protein Truncation><Protein phosphatase><Proteins><Putative RNA-Binding Region><RNA Binding><RNA Binding Domain><RNA Expression><RNA Recognition Motif><RNA Splicing><RNA bound><RNP Domain><RNP Motif><RNP-1 Signature><Regulation><Splicing><Tauopathies><Tertiary Protein Structure><Therapeutic><Toxic effect><Toxicities><Transcription><Transgenic Mice><Transgenic Organisms><Translating><United States><abnormally aggregated tau protein><aminoacid><brain tissue><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><developmental><epistatic relationship><filamentous tau inclusion><front temporal dementia><frontal lobe dementia><frontotemporal lobar dementia><frontotemporal lobe degeneration associated with dementia><gain of function><gene x gene interaction><genetic analysis><genetic epistases><genome mutation><glycogen synthase a kinase><health care><hydroxyalkyl protein kinase><loss of function><loss of function mutation><mRNA><memory dysfunction><microtubule associated protein tau aggregation><microtubule associated protein tau deposit><microtubule bound tau><microtubule-bound tau><model of animal><mouse model><murine model><mutant><name><named><naming><neural degeneration><neural dysfunction><neurodegeneration><neurodegenerative><neurodegenerative illness><neurological degeneration><neuronal><neuronal degeneration><neuropathologic tau><neuropathological tau><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><nuclear inhibitory polypeptide of protein phosphatase-1><overexpress><overexpression><paired helical filament of tau><phosphatase inhibitor 1><phosphorylase b kinase kinase><primary degenerative dementia><protein function><protein phosphatase inhibitor-1><self-aggregate tau><senile dementia of the Alzheimer type><tau><tau PHF><tau Proteins><tau accumulation><tau aggregate><tau aggregation><tau associated neurodegeneration><tau associated neurodegenerative process><tau expression><tau factor><tau fibrillization><tau filament><tau induced neurodegeneration><tau mediated neurodegeneration><tau neurodegenerative disease><tau neurofibrillary tangle><tau neuropathology><tau oligomer><tau paired helical filament><tau polymerization><tau-tau interaction><tauopathic neurodegenerative disorder><tauopathy><transgenic><translational impact><τ Proteins><τ aggregation><τ expression>