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Principal Investigator: David E Kang
Organization: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
Accumulation of toxic proteins (i.e. Aβ42 & tau) and dysfunctional mitochondria are associated with synaptic and neuronal loss in multiple neurodegenerative disorders, including Alzheimer’s disease (AD). Such clearance defects are thought to arise in large part from deficits in the autophagy-lysosome system. While mounting experimental evidence supports the notion that AD is a tauopathy at least in part driven Aβ, there is still a considerable knowledge gap in the way Aβ and tau pathogenesis are mechanistically connected. Our recently published and preliminary studies indicate that the Slingshot homolog-1 (SSH1) pathway constitutes a critical link between Aβ and tau pathogenesis. SSH1 is a protein phosphatase, classically known for its cofilin dephosphorylating activity. SSH1 is activated by oxidative stress (i.e. H2O2, Aβ, etc.) and/or intracellular Ca2+ elevation, which results in activation / dephosphorylation of cofilin. Activated cofilin can then sever F-actin (at the synapse) and/or translocate to mitochondria to promote mitochondria-mediated apoptosis. Likewise, we have found that activation of SSH1 and cofilin are required for Aβ42-induced mitochondrial dysfunction, synaptic loss, as wells as deficits in LTP and/or learning/memory in cellular and mouse models of A pathogenesis (APP/PS1). In support of these experimental findings, activated cofilin and SSH1/cofilin complexes are increased in APP/PS1 mouse brains as wells as in mitochondria of AD brains. In preliminary studies, we found that in addition to cofilin, SSH1 contains a modular and independent activity on the autophagy cargo receptor p62, which functions to regulate autophagy and tau clearance. By utilizing molecular, biochemical, cell biological, viral, and histochemical tools, we propose to (1) dissect the modular activity of SSH1 in p62-mediated autophagy and mitophagy; and (2) determine the role of SSH1 in p62-mediated autophagy and tauopathy in vivo.
Terms: <A β-42><A β42><A-beta 42><A-beta42><AD dementia><AD model><APP-PS1><APP/PS1><Abeta-42><Abeta42><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's brain><Alzheimer's disease brain><Alzheimer's disease model><Alzheimers Dementia><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-42><Amyloid beta-Protein><Amyloid beta42><Amyloid β><Amyloid β-42><Amyloid β-Peptide><Amyloid β-Protein><Amyloid β42><Amyloidβ-42><Amyloidβ42><Animal Model><Animal Models and Related Studies><Antimorphic mutation><Apoptosis><Apoptosis Pathway><Assay><Autophagocytosis><Aβ><Aβ-42><Aβ42><Binding><Binding Sites><Bioassay><Biochemical><Biological><Biological Assay><Brain><Brain Nervous System><C-terminal><Catalytic Core><Catalytic Domain><Catalytic Region><Catalytic Site><Catalytic Subunit><Cell Body><Cell model><Cells><Cellular model><Closure by Ligation><Co-Immunoprecipitations><Combining Site><Complex><Defect><Degenerative Neurologic Disorders><Dephosphorylation><Dominant Negative><Dominant-Negative Mutant><Dominant-Negative Mutation><Encephalon><F-Actin><Filamentous Actin><Gene Expression><GeneHomolog><Genetic Alteration><Genetic Change><Genetic defect><H2O2><Homolog><Homologous Gene><Homologue><Hydrogen Peroxide><Hydroperoxide><Impairment><Knowledge><Learning><Ligation><Link><Lysosomes><MT-bound tau><Mediating><Memory><Mice><Mice Mammals><Micro-tubule><Microtubules><Mitochondria><Molecular><Molecular Interaction><Murine><Mus><Mutation><Nerve Cells><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neurons><Outcome><Oxidative Stress><Oxidative Stress Induction><Pathogenesis><Pathway interactions><Phosphoprotein Phosphatase><Phosphoprotein Phosphatase-2C><Phosphoprotein Phosphohydrolase><Phosphorylation><Play><Primary Senile Degenerative Dementia><Process><Programmed Cell Death><Protein Dephosphorylation><Protein Phosphatase C><Protein Phosphatase Gene><Protein Phosphatase-1><Protein Phosphatase-2A><Protein Phosphorylation><Protein phosphatase><Proteins><Publishing><Reactive Site><Receptor Protein><Role><Synapses><Synaptic><System><Tauopathies><Testing><Transfection><Variant><Variation><Viral><a beta peptide><abeta><abnormally aggregated tau protein><alzheimer model><amyloid beta><amyloid-b protein><autophagy><beta amyloid fibril><biologic><cofilin><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><filamentous tau inclusion><genome mutation><hyper-phosphorylated tau><hyperphosphorylated tau><in vivo><indexing><insight><microtubule associated protein tau aggregation><microtubule associated protein tau deposit><microtubule bound tau><microtubule-bound tau><mitochondrial><mitochondrial dysfunction><model of animal><mouse model><murine model><mutant><nerve cell death><nerve cell loss><neurodegenerative illness><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal loss><neuropathologic tau><neuropathological tau><novel><paired helical filament of tau><pathway><primary degenerative dementia><receptor><self-aggregate tau><senile dementia of the Alzheimer type><social role><soluble amyloid precursor protein><synapse><tau><tau PHF><tau Proteins><tau accumulation><tau aggregate><tau aggregation><tau associated neurodegeneration><tau associated neurodegenerative process><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><tool><τ Proteins><τ aggregation>