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  98 human secreted proteinsUSPTO Application #: 20080051338Title: 98 human secreted proteins Abstract: The present invention relates to novel human secreted proteins and isolated nucleic acids containing the coding regions of the genes encoding such proteins. Also provided are vectors, host cells, antibodies, and recombinant methods for producing human secreted proteins. The invention further relates to diagnostic and therapeutic methods useful for diagnosing and treating diseases, disorders, and/or conditions related to these novel human secreted proteins. (end of abstract) Agent: Human Genome Sciences Inc. Intellectual Property Dept. - Rockville, MD, US Inventors: George A. Komatsoulis, Craig A. Rosen, Steven M. Ruben, Roxanne D. Duan, Paul A. Moore, Yanggu Shi, David W. LaFleur, Ying-Fei Wei, Jian Ni, Kimberly A. Florence, Paul E. Young, Laurie A. Brewer, Daniel R. Soppet, Gregory A. Endress, Reinhard Ebner, Henrik Olsen, Michael Mucenski USPTO Applicaton #: 20080051338 - Class: 514012000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 25 Or More Peptide Repeating Units In Known Peptide Chain Structure The Patent Description & Claims data below is from USPTO Patent Application 20080051338. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. application Ser. No. 10/204,337, filed May 22, 2003, now pending, which is a .sctn.371 National Phase filing of international patent application serial number PCT/US01/05569, filed Feb. 20, 2001, which claims benefit of priority to U.S. Provisional Application No. 60/183,571, filed on Feb. 18, 2000. The aforementioned applications are explicitly incorporated herein by reference in their entirety and for all purposes. REFERENCE TO SEQUENCE LISTING SUBMITTED VIA EFS-WEB [0002] This application was filed electronically via the USPTO EFS-WEB server, as authorized and set forth in MPEP .sctn.1730 II.B.2.(a)(A), and this electronic filing includes an electronically submitted sequence (SEQ ID) listing; the entire content of this sequence listing is herein incorporated by reference for all purposes. The sequence listing is identified on the electronically filed .txt file as follows: TABLE-US-00001 File Name Date of Creation Size (bytes) 220002065201.txt Feb. 15, 2007 8,192 FIELD OF THE INVENTION [0003] This invention relates generally to methods for screening for and treatment of neurodegenerative diseases and more specifically to methods of measuring aggregation in neurons of .alpha.-, .beta.-, and .gamma.-synucleins and treatments utilizing synuclein and peptides derived therefrom as anti-amyloidogenic agents in vivo. BACKGROUND OF THE INVENTION [0004] Parkinson's disease (PD), Alzheimer's disease (AD) and Lewy Body disease (LBD) are the most commonly found neurodegenerative disorders in the elderly population. Although their incidence continues to increase thus creating a serious public health problem, to date these disorders are neither curable nor preventable. Previous studies have shown that cognitive alterations seen with these disorders are most often associated with synaptic damage and that injury to the synapse might be associated with altered function of synaptic proteins. Among them, recent studies have pointed to .alpha.-synuclein, also known as the precursor of the non-A.beta. component of Alzheimer's disease amyloid (NACP) as a major player in the pathogenesis of these diseases. [0005] The neurodegenerative process in Parkinson's disease and Alzheimer's disease is characterized by extensive loss of selected neuronal populations accompanied by synaptic injury, astrogliosis and pathological hallmarks such as amyloid plaques, neurofibrillary tangles and neutrophil thread formation in Alzheimer's disease and the intraneuronal inclusions called Lewy bodies in Parkinson's disease. Parkinson's disease belongs to a heterogenous group of disorders presenting with parkinsonism and Lewy Body formation and which has been denominated Lewy body disease. Although the mechanisms triggering cell death and synaptic damage are unclear, the prevailing view is that neurodegeneration might result from gain of a toxic property of specific neuronal cell proteins, such as .alpha.-synuclein (in Parkinson's disease) and amyloid precursor protein (APP) (in Alzheimer's disease). In this regard, APP has been proposed to be centrally involved in Alzheimer's disease pathogenesis because mutations within this molecule are associated with familial forms of Alzheimer's disease, proteolytic products of APP processing abnormally accumulating in brains of Alzheimer's disease patients and overexpression of a mutant form of APP in transgenic mice mimics several aspects of Alzheimer's disease. [0006] .alpha.-Synuclein, which belongs to a larger family of molecules including .beta.- and .gamma.-synuclein, is a 140 amino acid synaptic protein which is a precursor of the 35 amino acid amyloidogenic molecule non-amyloid component (NAC). .alpha.-Synuclein has been implicated in Parkinson's disease because it is abundantly found in Lewy Bodies, its overexpression in transgenic mice leads to Parkinson's disease-like pathology, and mutations within this molecule are associated with familial Parkinson's disease. While the precise mechanism by which .alpha.-synuclein and APP might interact during events leading to neurodegeneration are unclear, several studies support the contention that .alpha.-synuclein is involved in Alzheimer's disease because it abnormally accumulates in synapses and dystrophic neurites surrounding the plaques in Alzheimer's disease brain and NAC is present in amyloid plaque cores and promotes A.beta. aggregation. Moreover, other studies have shown that both .alpha.-synuclein and A.beta. aggregate under similar experimental conditions, and in familial Alzheimer's disease and Down's syndrome there is formation of .alpha.-synuclein-immunoreactive Lewy Bodies. Furthermore, a combined form of Parkinson's disease and Alzheimer's disease has also been associated with the widespread formation of .alpha.-synuclein-immunoreactive Lewy Bodies. Taken together, these studies support the possibility that interactions between .alpha.-synuclein and APP might lead to enhanced amyloidogenesis and neurodegeneration in disorders such as Parkinson's disease and Alzheimer's disease. [0007] Several studies have suggested that neurons may be able to develop protective strategies against the neurotoxic effects of amyloid. For example, in neurodegenerative disorders associated with trinucleotide repeats, such as Frederick's ataxia, Myotonic dystrophy and Huntington's disease, formation of intraneuronal inclusion bodies might be protective, because the toxic proto-fibrils are sequestered. Similarly, in Parkinson's disease and Alzheimer's disease, is has been suggested that proto- rather than mature fibrils are neurotoxic. In this context, it is possible that the balance between amyloidogenic and anti-amyloidogenic molecules regulates neuronal survival. It is hypothesized that .beta.-synuclein, the non-amyloidogenic homologue of .alpha.-synuclein, which naturally lacks the NAC domain, may inhibit amyloidogenesis and neurodegeneration. .beta.-Synuclein is similar to .alpha.-synuclein in that it is abundantly expressed in the central nervous system, whereas .gamma.-synuclein is expressed mainly in the peripheral nervous system. The relationship between .alpha.-synuclein and .beta.-synuclein is strikingly similar to that of APP and its related protein APLP2 in that APLP2 is highly homologous with APP except for its A.beta. domain and that it is non-amyloidogenic. [0008] Human .alpha.-synuclein belongs to a larger family of synuclein proteins encoded by a gene on chromosome 4 and is highly abundant in the presynaptic terminals throughout the central nervous system (CNS). While the precise function of the synuclein superfamily of peptides is still unknown, several lines of evidence suggest potential roles in synaptic function and neural plasticity. Synelfin is the avian homologue to .alpha.-synuclein and PNP14 is the bovine homologue to human and murine .beta.-synuclein, a phosphoprotein encoded by a gene on chromosome 5. More recently, .gamma.-synuclein was isolated as a D3 synuclein-like molecule which was expressed predominantly in peripheral sympathetic neurons. .gamma.-Synuclein was later cloned from the EST library as the breast cancer specific gene (BCSG1) whose expression was observed in invasive types of breast cancer. Human .alpha.-synuclein was originally isolated from plaques of Alzheimer's disease brains as a 19-kD protein precursor of the highly hydrophobic 35-amino acid metabolite, non-amyloid component (NAC) of plaques. The NAC peptide can self-aggregate into fibrils and induces aggregation of the .beta.-amyloid peptide. [0009] Applicants seeks to establish that abnormal synuclein expression is involved in the pathogenesis of the neurodegenerative disorders Alzheimer's disease, Parkinson's disease and Lewy Body disease as well as determining the levels of .alpha.-, .beta.-, and .gamma.-synuclein mRNA in the brains of Lewy Body disease, Alzheimer's disease and Parkinson's disease in correlation with clinical and pathological indicators of these diseases. BRIEF SUMMARY OF THE INVENTION [0010] It is an object of the present invention to demonstrate the utility of .beta.-synuclein and peptides derived therefrom as anti-amyloidogenic agents in vitro as a method for screening for amyloidogenesis and in vivo as incorporated into novel pharmaceutical compositions and treatments strategies, i.e., gene therapy and peptide infusion, for treatment of neurodegenerative disease. [0011] It is another object of the present invention to provide methods for the use of novel transgenic animals comprising at least one transgene, portion, domain, mutant or derivative thereof that encodes a synuclein protein which is useful in screening for new anti-amyloidogenic agents. [0012] Through the methodologies of the present invention, Applicants seek to demonstrate that a critical balance between pro- and anti-amyloidogenic molecules exists that regulates amyloid formation and cell death in Alzheimer's disease and Parkinson's disease. To this end it is postulated that .beta.-synuclein, the non-amyloidogenic homologue of .alpha.-synuclein, is a negative modulator of .alpha.-synuclein and A.beta. aggregation, having neuroprotective properties against .alpha.-synuclein and A.beta. neurotoxicity and that .beta.-synuclein and agents derived therefrom block amyloidogenesis and neurodegeneration in vivo. The established hypothesis is that .beta.-synuclein may block A.beta. aggregation either by direct inhibition of A.beta. amyloidogenesis or indirectly via either .alpha.-synuclein or its 35 a.a. NAC region, inferring neuroprotective characteristics within the effected cells. Applicants seek to characterize the mechanisms by which .beta.-synuclein blocks .alpha.-synuclein and A.beta. aggregation and whether this mechanism offers protection to the cell against amyloid formation as seen in the pathologies of Alzheimer's disease and Parkinson's disease. [0013] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. [0014] All publications, patents, patent applications cited herein are hereby expressly incorporated by reference for all purposes. BRIEF DESCRIPTION OF THE DRAWINGS [0015] FIG. 1 is a schematic representation of .beta.-synuclein mutants .delta.1 and .delta.2 and .alpha.-synuclein. .beta.-synuclein lacks the part of the NAC domain corresponding to a.a. 73-83 of .alpha.-synuclein. [0016] FIG. 2 shows SDS-PAGE/Coomassie brilliant blue staining results from the analysis of .beta.-synuclein mutants .delta.1 and .delta.2 and .alpha.-synuclein incubated under high temperature conditions for the indicated times. [0017] FIG. 3 shows SDS-PAGE/Coomassie brilliant blue staining results of the incubation of .alpha.-synuclein alone or in the presence of either .beta.-synuclein or IgG under high temperature conditions for the indicated times. [0018] FIG. 4 shows a graph generated from the quantification of data of the ratio of .beta.-synuclein and .alpha.-synuclein aggregates (aggregation) versus monomers (non-aggregation) Continue reading... 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