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The PI3K/Akt/mTOR pathway has been shown to be involved in central nervous (CNS) system disorders including epilepsy, neurodegenerative diseases such as Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis through aberrant protein accumulation (autophagy, process of removal of such proteins may be dysregulated with pathway activation) and schizophrenia (through activation of GSK3b within the pathway).

Epilepsy
Epilepsy is a chronic neurologic seizure disorder characterized by repeated nervous seizures with interruption of normal brain activity. It is characterized by recurrent unprovoked seizures lasting from a few seconds to several minutes. Symptoms may include convulsions and loss of consciousness, blank staring, lip smacking or jerking movements of arms and legs. Epilepsy affects more than fifty million people worldwide and nearly three million people in the United States predicted to double by 2015. 30% of patients taking antiepileptic drugs continue to have seizures even while taking two or more antiepileptic drugs.

Tuberous sclerosis (TSC) is a syndrome attributable to mutations in either TSC1 or TSC2. Neurological manifestations are a predominant clinical feature and include early-onset epilepsy, mental retardation, developmental delay, and autism. Most neurological symptoms are thought to be attributable to the occurrence of cortical tubers which typically form at the gray-white matter junction. A cortical tuber is a region of the brain that develops abnormally through the formation of benign lesions that displace normal brain tissue. TSC is named after these growths. The TSC1 and TSC2 proteins form a relatively tight complex in cells which functions in the PI3K/Akt/mTOR signaling pathway (see P529 Signaling Pathway in Core Technology section of web site). Mutation of TSC1 or TSC2 causing TSC1 or TSC2 protein dysfunction leads to up-regulation of the PI3K/Akt/mTOR pathway. There are a variety of mouse models that have been developed to directly or in-directly affect TSC. These models include a murine model with loss of TSC1 in developing neurons, a kainate chemoconvulsant model which causes sustained neuronal depolarization, and a PTEN murine model which encodes a suppressor of the PI3K/Akt/mTOR pathway causing its activation. The PI3K/Akt/mTOR pathway is activated in each of these models with TORC1 inhibitors, namely rapamycin, showing a reduction of the number of spasms over time. We have also found that P529 to have activity in an epilepsy model.

Neurodegenerative Disease
Neurodegenerative diseases have been shown to have mutations in genes resulting in the aberrant accumulation of proteins. Alzheimer disease is one of the most serious health problems in the industrialized world. It is an insidious and progressive neurodegenerative disorder that accounts for the vast majority of age-related dementia and is characterized by global cognitive decline and the accumulation of ß-amyloid (Aß) precursor protein deposits and neurofibrillary tangles in the brain.

Parkinson's disease is the second most common neurodegenerative disease of adult onset. It is characterized by a severe loss of dopaminergic neurons in the brain and cytoplasmic inclusions consisting of insoluble α-synuclein protein aggregates (Lewy bodies) which lead to a progressive movement disorder including the classic triad of tremor, bradykinesia (slowed ability to start and continue movements, and impaired ability to adjust the body's position), and rigidity, with an average onset age between 50 and 60 years.

Amyotrophic lateral sclerosis (also known as motor neuron disease or Lou Gehrig's disease) is characterized by a rapidly progressive degeneration of motor neurons in the brain and spinal chord which ultimately leads to paralysis and premature death. Overall, the prevalence of Amyotrophic lateral sclerosis is low (approximately 5 in 100,000 individuals), but incidence increases with age, showing a peak between 55 and 75 years. Neuropathological features of Amyotrophic lateral sclerosis include intracellular accumulations of a variety of proteins found in Bunina bodies including ubiquitin-immunoreactive fibrils or aggregates, neurofilamentous aggregates, mutant copper/zinc superoxide dismutase (SOD1) aggregates, peripherin-immunoreactive aggregates and tau aggregates. Cognitive impairment and dementia coexist with Amyotrophic lateral sclerosis in at least 5% of the cases.

Huntington's disease is caused by degeneration of neurons clinically leading to involuntary movements, psychiatric symptoms, and dementia. Its prevalence is similar to that of Amyotrophic lateral sclerosis. Approximately 90% of Huntington's disease cases are hereditary and transmitted in an autosomal dominant fashion. The underlying gene defect, huntingtin, results in the accumulation of the huntingtin protein. Autophagy is a degradative mechanism for removal and turnover of proteins within a cell via a lysosomal system (spherical organelle that contains enzymes which digest proteins). As example, damaged proteins caused by cellular injury may be transferred to the autophagic pathway for removal. Overall, autophagy constitutes a fundamental survival strategy of cells. Disturbance of autophagy contributes to the pathogenesis of neurodegenerative disorders such as Amyotrophic lateral sclerosis, Parkinson`s disease, Huntington`s disease and Alzheimer`s disease. In recent years, progress has been achieved in elucidating the underlying biochemical events in autophagy as it relates to neurodegenerative disease. At least in part, activation of the PI3K/Akt/mTOR signaling pathway has been shown to inhibit autophagy in response to growth factor signals. Rapamycin has been shown to stimulate autophagy and further shown to aid in models of Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Of particular interest, there is data to support involvement of TORC2 signaling, not TORC1 signaling in Alzheimer's disease. As P529 inhibits both TORC1 and TORC2, it is possible that it would have activity in neurodegenerative diseases.

Schizophrenia
Disrupted-in-schizophrenia 1 (DISC1) is a susceptibility gene for major mental illnesses (schizophrenia, schizoaffective disorder, bipolar disorder, major depression and autism spectrum disorders), regulating multiple aspects of embryonic and adult neuron growth. Normally, DISC1 binds to glycogen synthase kinase 3b (GSK3b) inhibiting its activation. Mutation in DISC1 removes GSK3b block resulting in activation, phosphorylation of GSK3b indicating a direct involvement of the PI3K/Akt/mTOR pathway in mental illnesses. In animal models, blocking ion movement through the ion channels of neurons, preventing influx of calcium, can induce the characteristic behavioral changes in schizophrenia. In these studies, pharmacologic block of calcium ion channels results in the increase of phosphorylation of Akt (Ser-473) and S6.

P529 inhibits GSK3b phosphorylation, thereby capable of reversing the effect of mutation in DISC1 as well as inhibits the phosphorylation of both Akt (Ser-473) and S6, capable of reversing downstream effects of calcium ion blockage.

We are currently working with a number of academic groups to study P529 in neurodegenerative diseases and schizophrenia.
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