Presenilin associated membrane protein and uses thereof

Details Presenilin associated membrane protein and uses thereof Presenilin associated membrane protein and uses thereof

2000-03-31

2004-11-02

Reynolds, Deborah J. (Department: 1632)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C435S325000, C435S069100, C435S070100

Reexamination Certificate

active

06812337

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to the field of neurological and physiological dysfunctions associated with neuropsychiatric and developmental diseases, especially Alzheimer's Disease. More particularly, the invention is concerned with the identification of proteins associated with neuropsychiatric and developmental diseases, especially Alzheimer's Disease, and relates to methods of diagnosing these diseases, and to methods of screening for candidate compounds which modulate the interaction of a certain protein, specifically Presenilin Associated Membrane Protein (“PAMP”), with presenilin proteins.
BACKGROUND OF THE INVENTION
Alzheimer's Disease (AD) is a degenerative disorder of the human central nervous system characterized by progressive memory impairment and cognitive and intellectual decline during mid to late adult life (Katzman,
N Eng J Med
1986;314:964-973). The disease is accompanied by a constellation of neuropathologic features principal amongst which are the presence of extracellular amyloid or senile plaques, and neurofibrillary tangles in neurons. The etiology of this disease is complex, although in some families it appears to be inherited as an autosomal dominant trait. Genetic studies have identified three genes associated with the development of AD, namely: (1) &bgr;-amyloid precursor protein (&bgr;APP) (Chartier-Harlin et al.,
Nature
1991;353:844-846; Goate et al.,
Nature
1991;349:704-706; Murrell et al.,
Science
1991:254:97-99; Karlinsky et al.,
Neurology
1992;42:1445-1453; Mullan et al.,
Nature Genetics
1992;1:345-347); (2) presenilin-1 (PS1) (Sherrington et al.,
Nature
1995;375:754-760); and (3) presenilin-2 (PS2) (Rogaev et al.,
Nature
1995;376:775-778; Levy-Lehad et al.,
Science
1995; 269:970-973).
Abnormal processing of &bgr;APP with overproduction of amyloid-&bgr; is also a feature of other CNS diseases, including inherited and sporadic forms of amyloid angiopathy, which presents with intracerebral bleeding (Levy et al.,
Science
1990;248:1124-1126). Thus, abnormalities of presenilin proteins and PS-interacting proteins may affect these diseases as well.
The presenilin genes (PS1—PS1 and PS2—PS2) encode homologous polytopic transmembrane proteins that are expressed at low levels in intracellular membranes including the nuclear envelope, the endoplasmic reticulum the Golgi apparatus and some as yet uncharacterized intracytoplasmic vesicles in many different cell types including neuronal and non-neuronal cells (Sherrington et al., supra; Rogaev et al., supra, Levy-Lahad et al., supra; Doan et al.,
Neuron
1996;17:1023-1030; Walter et al.,
Molec. Medicine
1996;2:673-691; De Strooper et al.,
J. Biol. Chem
. 1997;272:3590-3598; Lehmann et al.,
J.Biol.Chem
. 1997;272:12047-12051; Li et al.,
Cell
1997;90:917-927). Structural studies predict that the presenilins contain between six and eight transmembrane (TM) domains organized such that the N-terminus, the C-terminus, and a large hydrophilic loop following the sixth TM domain are located in the cytoplasm or nucleoplasm, while the hydrophilic loop between TM1 and TM2 is located within the lumen of membranous intracellular organelles (Doan et al., 1996; De Strooper et al., 1997; et al., 1997).
Missense mutations in the PS1 and PS2 genes are associated with the inherited forms of early-onset AD (Sherrington et al.,
Nature
1995;375:754-760; Rogaev, et al.,
Nature
1995;376:775-778; Levy-Lahad et al,
Science
1995;269:970-973). Several lines of evidence have also suggested roles in developmental, apoptotic signalling and in the regulation of proteolytic cleavage of the &bgr;-amyloid precursor protein (&bgr;APP) (Levitan et al.,
Nature
1995;377:351-354; Wong et al.,
Nature
1997;387:288-292; Shen et al.,
Cell
1997;89:629-639; Wolozin et al.,
Science
1996;274:1710-1713; De Strooper et al.,
Nature
1998;391:387-390). Nevertheless, it remains unclear just how these putative functions are mediated, or how they relate to the abnormal metabolism of the &bgr;APP associated with PS1 and PS2 mutations (Martin et al.,
NeuroReport
995;7:217-220; Scheuner et al.,
Nature Med
. 1996;2:864-870; Citron et al.,
Nature Med
. 1997;3:67-72; Duff et al.,
Nature
1996;383:710-713; Borchelt et al.,
Neuron
1996;17:1005-1013).
P1 and PS2 interact specifically with at least two members of the armadillo family proteins; neuronal plakophilin-related armadillo protein (Paffenholtz et al.,
Differentiation
1997; 61: 293-304; Paffenholtz et al.,
Exp Cell Res
1999; 250: 452-464; Zhou et al.,
Neuroreport
1997; 8: 2085-2090) and &bgr;-catenin, that are expressed in both embryonic and post-natal tissues. Moreover, the domains of PS1 and PS2 that interact with these proteins have been identified. Mutations in PS1 and PS2 affect the translocation of &bgr;-catenin into the nucleus of both native cells and cells transfected with a mutant PS gene. These interactions and effects are described in detail in co-pending commonly assigned U.S. application Ser. No. 09/227,725, filed Jan. 8, 1999, the disclosure of which is incorporated herein by reference.
The identification and cloning of normal as well as mutant PS1 and PS2 genes and gene products are described in detail in co-pending commonly assigned U.S. application Ser. Nos. 08/431,048, filed Apr. 28, 1995; Ser. No. 08/496,841, filed Jun. 28, 1995; Ser. No. 08/509,359, filed Jul. 31, 1995; and Ser. No. 08/592,541, filed Jan. 26, 1996, the disclosures of which are incorporated herein by reference.
There is speculation that onset of AD may be associated with aberrant interactions between mutant presenilin proteins and normal forms of PS-interacting proteins, and these changes may increase or decrease interactions present with normal PS1, or cause interaction with a mutation-specific PS-interacting protein. Such aberrant interactions also may result from normal presenilins binding to mutant forms of the PS-interacting proteins. Therefore, mutations in the PS-interacting proteins may also be implicated in the development of AD.
While the identification of normal and mutant forms of PS proteins has greatly facilitated development of diagnostics and therapeutics, a need exists for new methods and reagents to more accurately and effectively diagnose and treat AD. In addition, further insights into PS proteins and their interaction with other components may lead to new diagnostic and treatment methods for other related CNS diseases.
SUMMARY OF THE INVENTION
Applicants have discovered that PS1 and PS2 interact specifically with a transmembrane protein, herein referred to as “Presenilin Associated Membrane Protein” or “PAMP”, which is expressed in multiple tissues (e.g., brain, kidney, lung, etc.). The product of this gene is therefore implicated in the biochemical pathways affected in Alzheimer's Disease, and may also have a role in other dementias, amyloid angiopathies, and developmental disorders such as spina bifida. This gene, therefore, presents a new therapeutic target for the treatment of Alzheimer's Disease and other neurologic diseases. In addition, PAMP nucleic acids, proteins and peptides, antibodies to PAMP, cells transformed with PAMP nucleic acids, and transgenic animals altered with PAMP nucleic acids that possess various utilities, as described herein for the diagnosis, therapy and continued investigation of Alzheimer's Disease and other neurodegenerative disorders. Furthermore, mutant PAMP nucleic acids, proteins, or peptides, cells transfected with vectors comprising mutant PAMP nucleic acids, transgenic animals expressing mutant PAMP or peptides thereof, and their use in studying Alzheimer's Disease and other neurodegenerative disorders, or developing improved diagnostic or therapeutic methods for such disorders, are presented herein.
Thus, the invention provides isolated and purified presenilin associated membrane protein (PAMP), or a functional fragment thereof, as well as nucleic acids encoding a PAMP. Preferred nucleotide and amino acid sequences are provided herein. The inven

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