Neurological disorders

Alzheimer's disease (AD)

Alzheimer's disease (AD) is a neurodegenerative disease that causes progressive loss of memory, judgement, and other cognitive processes. The hallmark of AD pathology is the deposition of beta-amyloid plaques and tau tangles. These abnormalities are implicated in the disruption of cellular communication, oxidative cell damage, and eventual cell death. Multiple genes are thought to contribute to AD suceptibility along with epigenetic and environmental factors. BARK1 (GRK2, ADRBK1) is a protein-serine/threonine kinase that can phosphorylate and desensitize the activated form of the beta-adrenergic receptor. BARK1 is a member of the GRKs, which function to phosphorylate GPCRs. Abnormal BARK1 expression has been implicated in AD and after cerebral hypoxia/ischemia. Moreover, GRKs have been shown to regulate the expression and function of the metabotropic glutamate receptor 5, which has been implicated in the pathogenesis of AD. Elevated BARK1 expression has been demonstrated in the early stages of nervous tissue damage in human AD patients and animal models of AD. Furthermore, in AD nervous tissue BARK1 expression is associated with damaged cellular constituents such as mitochondria and mitochondrial-derived lysosomes. In addition, elevated BARK1 expression is observed in damaged blood vessels and vascular cells in AD patients and has been observed in neurons that contain neurofibrillary tangles (NFT). Later stages of the disease display the significant down regulation of BARK1 expression, indicating that the kinase may play a role only in the early stages of AD pathogenesis.
 

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Bladder carcinomas (%CFC= -57, p<0.018); Brain glioblastomas (%CFC= +1376, p<0.0004); Brain oligodendrogliomas (%CFC= +3026, p<0.03); and Ovary adenocarcinomas (%CFC= +138, p<0.016). The COSMIC website notes an up-regulated expression score for BARK1 in diverse human cancers of 523, which is 1.1-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 62 for this protein kinase in human cancers was 1-fold of the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.06 % in 24916 diverse cancer specimens. This rate is only -19 % lower than the average rate of 0.075 % calculated for human protein kinases in general.

Highest percent mutation rates per 100 amino acids length in human cancers: 0.25 % in 589 stomach cancers tested; 0.25 % in 1270 large intestine cancers tested; 0.24 % in 603 endometrium cancers tested; 0.17 % in 864 skin cancers tested; 0.13 % in 548 urinary tract cancers tested; 0.08 % in 1512 liver cancers tested; 0.07 % in 881 prostate cancers tested; 0.06 % in 1824 lung cancers tested; 0.06 % in 1316 breast cancers tested; 0.03 % in 2082 central nervous system cancers tested.

None > 7 in 20,199 cancer specimens

Only 8 deletions, no insertions mutations or complex mutations are noted on the COSMIC website.