Methods for the identification, assessment, prevention, and treatment of neurological disorders and diseases using fndc5

Abstract

The invention provides methods for identifying, assessing, preventing, and treating neurological disorders and diseases using Fndc5 and modulators of Fndc5 expression or activity.

1 - 11 . (canceled) 
     
     
         12 . A method for assessing whether a subject is afflicted with a neurological disease or disorder or has a risk of developing a neurological disease or disorder comprising the steps of detecting the expression of the Fndc5 gene or the expression or activity of Fndc5 polypeptide in a sample of a subject, wherein a decrease in the expression of the Fndc5 gene or a decrease in the expression or activity of the Fndc5 polypeptide compared to a control indicates the presence of a neurological disease or disorder or the risk of developing a neurological disease or disorder in the subject, optionally wherein the sample is selected from the group consisting of whole blood, serum, plasma, saliva, cerebrospinal fluid, spinal fluid, and neural tissue. 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 12 , wherein the expression of the Fndc5 polypeptide is detected
 a) using a reagent which specifically binds with the protein, optionally wherein the reagent is selected from the group consisting of an antibody, an antibody derivative, and an antibody fragment; or   b) by detecting the presence in the sample of a transcribed polynucleotide or portion thereof, optionally i) wherein the transcribed polynucleotide is an mRNA or a cDNA, ii) wherein the step of detecting further comprises amplifying the transcribed polynucleotide, or iii) wherein the level of expression of the marker in the sample is assessed by detecting the presence in the sample of a transcribed polynucleotide which anneals with Fndc5 or anneals with a portion of an Fndc5 polynucleotide under stringent hybridization conditions.   
     
     
         15 . The method of  claim 12 , wherein the Fndc5 polypeptide is selected from the group of polypeptides consisting of:
 a) a polypeptide encoded by a nucleic acid molecule comprising a nucleotide sequence encoding a fragment of the FNDC5 polypeptide of SEQ ID NO: 2, wherein said fragment lacks the C-terminal domain sequence of said FNDC5 polypeptide, and wherein said polypeptide has one or more of the biological activities of said FNCD5 polypeptide;   b) a polypeptide encoded by a nucleic acid molecule comprising a nucleotide sequence encoding an amino acid sequence that is at least 70% identical to the amino acid sequence of residues 73-140 of the FNDC5 polypeptide of SEQ ID NO:2, wherein said polypeptide does not encode the C-terminal domain sequence of said FNDC5 polypeptide, and wherein said polypeptide has one or more of the biological activities of said FNCD5 polypeptide;   c) a polypeptide which is a fragment of the FNDC5 polypeptide of SEQ ID NO: 2, which fragment is optionally fused to one or more heterologous polypeptides at its N-terminus and/or C-terminus, wherein said fragment consists of a sequence of amino acids in between residues 1 and 150 of SEQ ID NO: 2, and wherein said fragment has one or more of the biological activities of said FNCD5 polypeptide;   d) a polypeptide which is a fragment of the FNDC5 polypeptide of SEQ ID NO: 4, 6 or 8, wherein said fragment is optionally fused to one or more heterologous polypeptides at its N-terminus and/or C-terminus, and wherein said fragment has one or more of the biological activities of said FNCD5 polypeptide;   e) a polypeptide fragment of an Fndc5 protein comprising at least one fibronectin domain and is not full-length Fndc5;   f) a polypeptide fragment of an Fndc5 protein comprising at least one fibronectin domain and which lacks one or more functional domain(s) selected from the group consisting of signal peptide, hydrophobic, and C-terminal domains;   g) a polypeptide comprising an amino acid sequence that is at least 70% identity to the amino acid sequence comprising residues 73-140 of SEQ ID NO:2, residues 30-140 of SEQ ID NO:2 or residues 29-140 of SEQ ID NO:2 and which lacks one or more functional domain(s) of an Fndc5 protein selected from the group consisting of signal peptide, hydrophobic, and C-terminal domains;   h) a polypeptide comprising an amino acid sequence that is at least 70% identity to the amino acid sequence comprising residues 73-140 of SEQ ID NO:2, residues 30-140 of SEQ ID NO:2 or residues 29-140 of SEQ ID NO:2 and which is less than 195 amino acids in length;   i) a polypeptide consisting essentially of an amino acid sequence that is at least 70% identity to the amino acid sequence comprising residues 73-140 of SEQ ID NO:2, residues 30-140 of SEQ ID NO:2 or residues 29-140 of SEQ ID NO:2;   j) a polypeptide fragment of SEQ ID NO:2 comprising residues 73-140 of SEQ ID NO:2, residues 30-140 of SEQ ID NO:2 or residues 29-140 of SEQ ID NO:2 and which is not full-length;   k) a polypeptide fragment of SEQ ID NO:2 consisting essentially of residues 73-140 of SEQ ID NO:2, residues 30-140 of SEQ ID NO:2 or residues 29-140 of SEQ ID NO:2;   l) a polypeptide which is encoded by a nucleic acid molecule comprising a nucleotide sequence encoding at least one fibronectin domain of an Fndc5 protein and does not encode full-length Fndc5;   m) a polypeptide fragment of an Fndc5 protein which is encoded by a nucleic acid molecule comprising a nucleotide sequence encoding at least one fibronectin domain and which does not encode one or more functional domain(s) selected from the group consisting of signal peptide, hydrophobic, and C-terminal domains;   n) a polypeptide which is encoded by a nucleic acid molecule comprising a nucleotide sequence encoding an amino acid sequence that is at least 70% identical to the amino acid sequence of residues 73-140 of SEQ ID NO:2, residues 30-140 of SEQ ID NO:2 or residues 29-140 of SEQ ID NO:2 and which does not encode one or more functional domain(s) of an Fndc5 protein selected from the group consisting of signal peptide, hydrophobic, and C-terminal domains;   o) a polypeptide which is encoded by a nucleic acid molecule comprising a nucleotide sequence encoding an amino acid sequence that is at least 70% identical to the amino acid sequence of residues 73-140 of SEQ ID NO:2, residues 30-140 of SEQ ID NO:2 or residues 29-140 of SEQ ID NO:2 and which is less than 630 nucleotides in length;   p) a polypeptide which is encoded by a nucleic acid molecule consisting essentially of a nucleotide sequence encoding an amino acid sequence having at least 70% identity to the amino acid sequence of residues 73-140 of SEQ ID NO:2, residues 30-140 of SEQ ID NO:2 or residues 29-140 of SEQ ID NO:2;   q) a polypeptide which is encoded by a nucleic acid molecule comprising a nucleotide sequence encoding an amino acid sequence that is at least 70% identical to the amino acid sequence of residues 73-140 of SEQ ID NO:2, residues 30-140 of SEQ ID NO:2 or residues 29-140 of SEQ ID NO:2 and which does not encode the full-length amino acid sequence of SEQ ID NO:2;   r) a polypeptide which is encoded by a nucleic acid molecule comprising a nucleotide sequence encoding the amino acid sequence of residues 73-140 of SEQ ID NO:2, residues 30-140 of SEQ ID NO:2 or residues 29-140 of SEQ ID NO:2 and which does not encode the full-length amino acid sequence of SEQ ID NO:2;   s) a polypeptide which is encoded by a nucleic acid molecule consisting essentially of a nucleotide sequence encoding the amino acid sequence of residues 73-140 of SEQ ID NO:2, residues 30-140 of SEQ ID NO:2 or residues 29-140 of SEQ ID NO:2;   t) a polypeptide which is encoded by a nucleic acid molecule comprising a nucleotide sequence which is at least 70% identical to the nucleotide sequence of nucleotides 217-420 of SEQ ID NO:1, SEQ ID NO:15, nucleotides 88-420 of SEQ ID NO:1, or nucleotides 85-420 of SEQ ID NO:1 and which does not encode one or more functional domain(s) of an Fndc5 protein selected from the group consisting of signal peptide, hydrophobic, and C-terminal domains; and   u) a polypeptide which is encoded by a nucleic acid molecule consisting essentially of a nucleotide sequence which is at least 70% identical to the nucleotide sequence of nucleotides 217-420 of SEQ ID NO:1, SEQ ID NO:15, nucleotides 88-420 of SEQ ID NO:1, or nucleotides 85-420 of SEQ ID NO:1; and   v) a polypeptide that is a fragment of SEQ ID NO: 2 which consists of about amino acids 30 to 140 or 73-140 of SEQ ID NO: 2, wherein said fragment is optionally fused to one or more heterologous polypeptides at its N-terminus and/or C-terminus,   optionally wherein the one or more of the biological activities of FNDC5 polypeptide is selected from the group consisting of 1) increasing BDNF expression in the central and/or peripheral nervous system; 2) increasing activity-induced immediate-early gene expression in neurons; 3) increasing neuronal survival; 4) decreasing neurological lesion formation; 5) increasing neurite outgrowth; 6) increasing synaptogenesis; 7) increasing synaptic plasticity; 8) decreasing neuronal mitochondrial dysfunction; 9) increasing dendritic arborization; 10) increasing neuronal differentiation; and 11) increasing neuronal migration.   
     
     
         16 . The method of  claim 12 , wherein the Fndc5 polypeptide:
 a) is more than 65 amino acids in length and less than 135 amino acids in length;   b) is between 70 and 125 amino acids in length;   c) is less than 195 amino acids in length;   d) comprises a fibronectin domain;   e) is glycosylated or pegylated, optionally wherein at least one glycosylated amino acid residue corresponds to asparagine at position 36 and/or the asparagine at position 81 of SEQ ID NO:2;   f) comprises an amino acid sequence that is heterologous to said FNDC5 polypeptide, optionally wherein said heterologous amino acid sequence is an Fc domain, an IgG1 Fc domain, an IgG2 Fc domain, an IgG3 Fc domain, and IgG4 Fc domain, a dimerization domain, an oligomerization domain, an agent that promotes plasma solubility, albumin, a signal peptide, a peptide tag, a 6-His tag, a thioredoxin tag, a hemaglutinin tag, a GST tag, or an OmpA signal sequence tag; and/or   g) can cross the blood-brain barrier.   
     
     
         17 - 19 . (canceled) 
     
     
         20 . The method of  claim 12 , wherein the subject is a human and/or the neurological disease or disorder would benefit from decreased neuronal cell death and/or increased neuronal survival, optionally wherein the neurological disease or disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick's disease, Kuf's disease, Lewy body disease, neurofibrillary tangles, Rosenthal fibers, Mallory's hyaline, senile dementia, myasthenia gravis, Gilles de la Tourette's syndrome, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), epilepsy, Creutzfeldt-Jakob disease, deafness-dytonia syndrome, Leigh syndrome, Leber hereditary optic neuropathy (LHON), parkinsonism, dystonia, motor neuron disease, neuropathy-ataxia and retinitis pimentosa (NARP), maternal inherited Leigh syndrome (MILS), Friedreich ataxia, hereditary spastic paraplegia, Mohr-Tranebjaerg syndrome, Wilson disease, sporatic Alzheimer's disease, sporadic amyotrophic lateral sclerosis, sporadic Parkinson's disease, autonomic function disorders, hypertension, sleep disorders, neuropsychiatric disorders, depression, schizophrenia, schizoaffective disorder, korsakoff's psychosis, mania, anxiety disorders, phobic disorder, learning or memory disorders, amnesia or age-related memory loss, attention deficit disorder, dysthymic disorder, major depressive disorder, obsessive-compulsive disorder, psychoactive substance use disorders, panic disorder, bipolar affective disorder, severe bipolar affective (mood) disorder (BP-1), migraines, hyperactivity and movement disorders. 
     
     
         21 - 51 . (canceled)