Targeting Synaptogyrin-3 in Tauopathy Treatment

Abstract

The invention relates to identification of synaptogyrin-3 as a target for treating or inhibiting progression of tauopathies or symptoms of tauopathies. In particular, synaptogyrin-3 inhibitors for use as a medicament in general, and for treating or inhibiting progression of tauopathies or symptoms of tauopathies are envisaged. The invention further relates to methods for identification of or for screening for inhibitors of synaptogyrin-3.

1 . A method of treating or inhibiting progression of a tauopathic disorder in a subject, the method comprising:
 treating the subject with a synaptogyrin-3 inhibitor.   
     
     
         2 . The method according to  claim 1 , wherein the synaptogyrin-3 inhibited by the synaptogyrin-3 inhibitor is human synaptogyrin-3. 
     
     
         3 . The method according to  claim 1 , wherein the synaptogyrin-3 inhibitor is selected from the group consisting of an antibody or a fragment thereof binding to synaptogyrin-3, an alpha-body, a nanobody, an intrabody, an aptamer, a DARPin, an affibody, an affitin, an anticalin, and a monobody. 
     
     
         4 . The method according to  claim 1 , wherein the synaptogyrin-3 inhibitor blocks binding of synaptogyrin-3 to the N-terminal region of the Tau protein. 
     
     
         5 . The method according to  claim 3 , wherein the antibody or fragment thereof, the alpha-body, the nanobody, the intrabody, the aptamer, the DARPin, the affibody, the affitin, the anticalin, or the monobody specifically binds at least one intraneuronally exposed region of synaptogyrin-3. 
     
     
         6 . The method according to  claim 5 , wherein the intraneuronally exposed region of synaptogyrin-3 is selected from the group consisting of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4. 
     
     
         7 . The method according to  claim 1 , wherein the tauopathic disorder is selected from the group consisting of Alzheimer's disease, progressive supranuclear palsy (PSP), progressive supranuclear palsy-parkinsonism (PSP-P), Richardson's syndrome, argyrophilic grain disease, corticobasal degeneration Pick's disease, frontotemporal dementia with parkinsonism associated with chromosome 17 (FTDP-17), post-encephalitic parkinsonism, Parkinson's disease complex of Guam, Guadeloupean parkinsonism, Huntington disease, Down's syndrome, dementia pugilistica, familial British dementia, familial Danish dementia, myotonic dystrophy, Hallevorden-Spatz disease, Niemann Pick type C, chronic traumatic encephalopathy, tangle-only dementia, white matter tauopathy with globular glial inclusions, subacute sclerosing panencephalitis, SLC9A6-related mental retardation, non-Guamanian motor neuron disease with neurofibrillary tangles, neurodegeneration with brain iron accumulation, Gerstmann-Sträussler-Scheinker disease, frontotemporal lobar degeneration, diffuse neurofibrillary tangles with calcification, chronic traumatic encephalopathy, amyotrophic lateral sclerosis of Guam, amyotrophic lateral sclerosis and parkinsonism-dementia complex, prion protein cerebral amyloid angiopathy, and progressive subcortical gliosis. 
     
     
         8 . The method according to  claim 1 , wherein the symptom of the tauopathic disorder is selected from the group of mild cognitive impairment, dementia, cognitive decline, decline of motor function, oculomotor and bulbar dysfunction, synaptic dysfunction, neurotoxicity, neuronal degeneration, neuronal dysfunction, synapse loss, and amyloid deposition. 
     
     
         9 . The method according to  claim 8 , wherein the synaptic dysfunction is pre-synaptic dysfunction. 
     
     
         10 . An in vitro method for determining that a compound inhbits a synaptogyrin-3, said method comprising the steps of:
 i) providing synaptogyrin-3, or a fragment of synaptogyrin-3 comprising one or more of the intraneuronally exposed regions of synatogyrin-3;   ii) providing Tau protein, or a fragment of Tau comprising the N-terminal region;   iii) providing a compound that is candidate for being a synaptogyrin-3 inhibitor;   iv) contacting the synaptogyrin-3 or fragment thereof provided in i) with the Tau protein or fragment thereof provided in ii) in the presence and absence of the compound provided in iii);   v) determining that the compound reduces binding of the Tau protein or fragment thereof to synaptogyrin-3 or fragment thereof as compared to identical conditions but for the presence of the compound.   
     
     
         11 . The method according to  claim 10 , wherein the compound specifically binds to synaptogyrin-3. 
     
     
         12 . The method according to  claim 10  wherein the synaptogyrin-3 or fragment thereof is provided on isolated synaptic vesicles, on virus-like particles, or in liposomes. 
     
     
         13 . The method according to  claim 10  wherein the Tau protein or fragment thereof is immobilized on a solid carrier. 
     
     
         14 . The method according to  claim 13  wherein the solid carrier is magnetic. 
     
     
         15 . The method according to  claim 14  wherein the synaptic vesicle, the virus-like particle or the liposome is immobilized on a solid carrier. 
     
     
         16 . The method according to  claim 10  wherein the synaptogyrin-3 or fragment thereof and the Tau protein or fragment thereof is provided in a neuronal cell. 
     
     
         17 . The method according to  claim 10  wherein the binding of the synaptogyrin-3 or fragment thereof to the Tau protein or fragment thereof is determined by immunologic or radiologic detection, co-sedimentation, co-immunoprecipitation, or electron microscopy. 
     
     
         18 . An in vitro method for identifying a synaptogyrin-3 inhibitor, said method comprising the steps of:
 i) providing cells expressing synaptogyrin-3 or a fragment of synaptogyrin-3 comprising one or more of the intraneuronally exposed regions of synatogyrin-3;   ii) providing a synaptogyrin-3-specific compound that is candidate for being an inhibitor of synaptogyrin-3 expression;   iii) administering a compound provided in ii) to the cells provided in i); and   iv) determining that the compound reduces the expression of synaptogyrin-3 or fragment thereof as compared to identical conditions but for the but or the presence of the compound.   
     
     
         19 . A method of blocking the binding of synaptogyrin-3 to the N-terminal region of the Tau protein in a subject, the method comprising:
 determining that the subject is suffering from pathological Tau-induced presynaptic dysfunction; and   treating the subject with a synaptogyrin-3 inhibitor selected from the group consisting of an antibody or a fragment thereof binding to synaptogyrin-3, an alpha-body, a nanobody, an intrabody, an aptamer, a DARPin, an affibody, an affitin, an anticalin, and a monobody.