A new study from the Scripps Institute in Florida has identified regulator of BACE1, a protein that has been implicated in progression of Alzheimer’s disease (AD). The study, published in an advance online edition of the Journal of Biological Chemistry showed that a protein called Rheb (ras homolog enriched in brain) can reduce levels of BACE1 and may hold the key to future drug targets for Alzheimer’s disease.
BACE1 (β-site amyloid precursor protein (APP)-cleaving enzyme 1) is an enzyme that has been shown to kick off amyloid β (Aβ) production via amyloidogenic processing of amyloid precursor protein (APP). Aβ generation from neurons and deposition is widely accepted to be pivotal to development of Alzheimer’s disease. BACE1 protein levels are raised in AD brain; however this does not appear to be regulated via up-regulation of transcription of the gene that encodes BACE1 to messenger RNA (mRNA), the intermediary between gene and protein, but to be a direct effect on protein production. Rheb is a protein belonging to a family called GTPases and has recently been shown to protect neurons in Parkinson’s disease and may be important in neural plasticity. It is known to be important in regulating turnover of proteins via pathway known as mTOR, which is involved in many human diseases including neurodegenerative disorders. However, Rheb also has some mTOR-independent effects.
Given the known effects of Rheb on protein turnover and its potential role in neural plasticity, it seemed reasonable to enquire whether Rheb could influence expression of BACE1 protein. In a combination of in vitro cell line studies and in vivo mouse studies, the researchers showed that Rheb could down-regulate expression of BACE1. This down-regulation was not mediated via any change in mRNA levels but instead was due to a direct physical interaction between Rheb and BACE1 proteins which resulted in a reduction of BACE1 half-life and accelerated degradation of BACE1 protein. This Rheb-mediated degradation of BACE1 was independent of mTOR but dependent on GTP. It was mediated via both lysosomal and proteosomal pathways. Intriguingly, protein expression studies on AD post-mortem brains revealed significant loss of Rheb levels compared to non-AD brains. This reduction in Rheb correlated with increased BACE1.
Thus this study identifies Rheb as an inhibitor of BACE1 via a number of mechanisms in a pathway that may have profound implications for ageing brain biology and disease. A lot more research lies ahead to clarify the mechanisms at work, but this research holds promise for effective drug therapies in the future for AD.
Sources
Shahani N, Pryor W, Swarnkar S, Kholodilov N, Thinakaran G, Burke RE, et al. Rheb GTPase Regulates β-Secretase Levels and Amyloid β Generation. Journal of Biological Chemistry. 2013 Dec; Available from: http://dx.doi.org/10.1074/jbc.m113.532713.
Press release: http://www.scripps.edu/news/press/2014/2...aniam.html
BACE1 (β-site amyloid precursor protein (APP)-cleaving enzyme 1) is an enzyme that has been shown to kick off amyloid β (Aβ) production via amyloidogenic processing of amyloid precursor protein (APP). Aβ generation from neurons and deposition is widely accepted to be pivotal to development of Alzheimer’s disease. BACE1 protein levels are raised in AD brain; however this does not appear to be regulated via up-regulation of transcription of the gene that encodes BACE1 to messenger RNA (mRNA), the intermediary between gene and protein, but to be a direct effect on protein production. Rheb is a protein belonging to a family called GTPases and has recently been shown to protect neurons in Parkinson’s disease and may be important in neural plasticity. It is known to be important in regulating turnover of proteins via pathway known as mTOR, which is involved in many human diseases including neurodegenerative disorders. However, Rheb also has some mTOR-independent effects.
Given the known effects of Rheb on protein turnover and its potential role in neural plasticity, it seemed reasonable to enquire whether Rheb could influence expression of BACE1 protein. In a combination of in vitro cell line studies and in vivo mouse studies, the researchers showed that Rheb could down-regulate expression of BACE1. This down-regulation was not mediated via any change in mRNA levels but instead was due to a direct physical interaction between Rheb and BACE1 proteins which resulted in a reduction of BACE1 half-life and accelerated degradation of BACE1 protein. This Rheb-mediated degradation of BACE1 was independent of mTOR but dependent on GTP. It was mediated via both lysosomal and proteosomal pathways. Intriguingly, protein expression studies on AD post-mortem brains revealed significant loss of Rheb levels compared to non-AD brains. This reduction in Rheb correlated with increased BACE1.
Thus this study identifies Rheb as an inhibitor of BACE1 via a number of mechanisms in a pathway that may have profound implications for ageing brain biology and disease. A lot more research lies ahead to clarify the mechanisms at work, but this research holds promise for effective drug therapies in the future for AD.
Sources
Shahani N, Pryor W, Swarnkar S, Kholodilov N, Thinakaran G, Burke RE, et al. Rheb GTPase Regulates β-Secretase Levels and Amyloid β Generation. Journal of Biological Chemistry. 2013 Dec; Available from: http://dx.doi.org/10.1074/jbc.m113.532713.
Press release: http://www.scripps.edu/news/press/2014/2...aniam.html
