Compositions and Methods for Modulating PGC-1Alpha to Treat Neurological Diseases and Disorders

Abstract

The present invention provides methods for modulating mitochondrial function, modulating lesion formation in the brain, modulating neurite growth, modulating neuronal degeneration, and treating and preventing neurological diseases or disorders comprising modulating the expression of activity of PGC-1α. The present invention also provides an animal, e.g., transgenic mouse, in which the PGC-1α gene is misexpressed. Methods for identifying compounds which are capable of treating or preventing a neurological disease or disorder are also described.

1 - 43 . (canceled) 
     
     
         44 . A method for treating or preventing a neurological disease or disorder in a subject comprising the step of administering to said subject a peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) modulator,
 wherein the PGC-1α modulator increases PGC-1α expression or activity, and 
 wherein the modulator is a PGC-1α polypeptide comprising the amino acid sequence of SEQ ID NO: 2 or a portion thereof, 
 such that said polypeptide or portion thereof maintains the ability to modulate one or more of the following biological activities: mitochondrial function; the activity or expression of a mitochondrial gene selected from the group consisting of LDH2, Ndufb5, COX6a1, and ATP5j; the activity or expression of a neuronal gene selected from the group consisting of NF—H, NF-M, MOBP, ATPα1, and ATP1α2; lesion formation; neurite formation; neurite growth; neuronal degeneration; body weight; energy expenditure; gluconeogenesis; and interaction with nuclear hormone receptors, 
 such that the neurological disease or disorder is treated or prevented. 
 
     
     
         45 . The method of  claim 44 , wherein the PGC-1α polypeptide or portion thereof comprises an amino acid sequence which is at least 90 percent identical to the amino acid sequence of SEQ ID NO: 2. 
     
     
         46 . The method of  claim 44 , wherein the PGC-1α polypeptide or portion thereof is encoded by a nucleic acid molecule which hybridizes to a complement of a nucleic acid molecule consisting of SEQ ID NO:1 at 6×SSC at 45° C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 65° C. 
     
     
         47 . The method of  claim 44 , wherein the PGC-1α polypeptide or portion thereof further comprises a heterologous polypeptide. 
     
     
         48 . A method for treating or preventing a neurological disease or disorder in a subject comprising the step of administering to said subject a PGC-1α modulator,
 wherein the PGC-1α modulator increases PGC-1α expression or activity, and 
 wherein the modulator is a PGC-1α nucleic acid comprising the nucleotide sequence of SEQ ID NO:1, or a portion thereof, 
 such that said polypeptide or portion thereof maintains the ability to modulate one or more of the following biological activities: mitochondrial function; the activity or expression of a mitochondrial gene selected from the group consisting of LDH2, Ndufb5, COX6a1, and ATP5j; the activity or expression of a neuronal gene selected from the group consisting of NF—H, NF-M, MOBP, ATPα1, and ATP1α2; lesion formation; neurite formation; neurite growth; neuronal degeneration; body weight; energy expenditure; gluconeogenesis; and interaction with nuclear hormone receptors, 
 such that the neurological disease or disorder is treated or prevented. 
 
     
     
         49 . The method of  claim 48 , wherein the PGC-1α nucleic acid or portion thereof comprises a nucleic acid sequence which is at least 90 percent identical to the nucleic acid sequence of SEQ ID NO:1. 
     
     
         50 . The method of  claim 48 , wherein the PGC-1α nucleic acid or portion thereof further encodes a heterologous polypeptide. 
     
     
         51 . The method of  claim 44  or  48 , 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, deamess-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—I), migraines, hyperactivity and movement disorders. 
     
     
         52 . The method of  claim 44  or  48 , wherein the neurological disease or disorder is Parkinson's disease. 
     
     
         53 . The method of  claim 44  or  48 , wherein the subject is human. 
     
     
         54 . The method of  claim 44  or  48 , wherein said modulator is administered in a pharmaceutically acceptable formulation. 
     
     
         55 . The method of  claim 44  or  48 , wherein the PGC-1α modulator modulates mitochondrial function. 
     
     
         56 . The method of  claim 55 , wherein mitochondrial function is modulated in the brain. 
     
     
         57 . The method of  claim 44  or  48 , wherein the PGC-1α modulator modulates lesion formation in the brain. 
     
     
         58 . The method of  claim 44  or  48 , wherein the PGC-1α modulator modulates neurite growth.