REPORT
Autophagic activity was also necessary for the generation of synaptic overgrowth, indicating that autophagy may play a crucial role in neuronal atrophy in FTD.
AUTOPHAGY AND NEURODEGENERATION Parkinson’s disease (PD) is a degenerative disorder of the central nervous system in which dopaminergic neurons in the substantia nigra (part of the midbrain) become progressively damaged over many years. It is the most common movement disorder in humans and is characterised by the accumulation of the protein α-synuclein in neurons. Over-expression of α-synuclein is sufficient to cause PD, indicating that α-synuclein accumulation is toxic. Studies in Professor Rubinsztein’s laboratory have shown that α-synuclein inhibits autophagy and have proposed that deficiency in autophagy may contribute to the biology of the disease. Huntington’s disease (HD) is a
progressive, autosomal-dominant neurodegenerative disorder that affects muscle coordination and leads to cognitive decline and psychiatric problems. It is caused by the expansion of CAG trinucleotide repeats in the huntingtin gene, which is translated into an expanded polyglutamine tract in the N-terminus of the huntingtin protein. This toxic aggregate-prone protein has been shown to be an autophagy substrate. In 2005, results from Professor
Rubinsztein’s laboratory showed that lithium induces autophagy in an mTOR-independent way and thereby enhances the clearance of mutant huntingtin. This provided a rationale to test the mTOR inhibitor rapamycin (which induces mTOR-dependent autophagy) in combination with lithium for HD patients, an approach already showing promise in HD fly models. Furthermore, following screening of US
Food and Drug Administration (FDA)- approved drugs to identify new autophagy- inducing agents, clonidine and rilmenidine (both used for treatment of hypertension) have been proposed as potential candidates, as they both induce autophagy, perhaps by reducing cAMP levels, in an mTOR- independent manner. Taken together, promoting the clearance of
aggregate-prone toxic proteins via pharmacological induction of autophagy may provide a useful mechanism for protecting against the damaging effect of these proteins in patients with neurodegenerative diseases such as AD and HD.
AUTOPHAGY AND ANTI-LEUKAEMIA TREATMENT Chronic myeloid leukaemia (CML) is characterised by the Bcr-Abl fusion protein, a constitutively active tyrosine kinase that mimics growth factor activation in many ways. Treatment of CML has been revolutionised by c-Abl-specific tyrosine kinase inhibitors (TKIs) such as imatinib, which is capable of
724 THE BIOMEDICAL SCIENTIST
Treatment of chronic myeloid leukaemia has been revolutionised by c-Abl-specific tyrosine kinase inhibitors such as imatinib.
inhibiting Bcr-Abl kinase activity and induces cytogenetic and molecular responses in patients. However, minimal residual disease persistence, caused by CML stem cells that survive TKI treatment, is an ongoing problem in the clinic. Collaborative work from Professor Bruno Calabretta and Professor Tessa Holyoake has shown that TKI treatment induces autophagy in CML stem/progenitor cells (presented by Vignir Helgason). Of clinical importance, pharmacological autophagy inhibition led to near complete elimination of persistent CML stem cells when combined with TKI treatment in long- term stem cell assay. This provided a rationale for CHOICES (CHlorOquine and Imatinib Combination to Eliminate Stem cells), a randomised phase II clinical trial in which the combination of imatinib with HCQ- mediated autophagy inhibition in CML patients is being tested. Furthermore, by examining expression levels of some key autophagy genes, Dr Xiaoyan Jiang presented data illustrating that ATG4B, a core autophagy protein, is critical to the survival of CML stem/progenitors cells,
‘Pharmacological induction of autophagy may prove useful in protecting against the damaging effect of aggregate-prone toxic proteins in patients with neurodegenerative diseases’
suggesting that specific inhibition of a key autophagy regulator may provide an option for specific autophagy targeting with a small molecule. In addition, by analysing response rates of CML patients retrospectively, it was shown that ATG4B may predict clinical outcomes in CML patients treated with imatinib.
BOVINE MAMMARY GLAND DEVELOPMENT Dr Malgorzata Gajewska has been studying the involvement of autophagy in remodelling the bovine mammary gland. While most tissues and organs undergo massive growth in the early stages of development, the bovine mammary gland undergoes intensive remodelling during the lactation cycle (after the animal has reached maturity). Therefore, the mammary gland has proved a very good model for studying processes involved in development and differentiation. In vitro studies showed that enhanced autophagy is observed at the end of lactation and during dry periods. Interestingly, enhanced transcription of autophagy genes in bovine mammary epithelial cells may depend on, or be mediated by, sex hormones such as 17 β-oestadiol and progesterone. This emphasises the importance of tight autophagy gene regulation in development and underlines the diverse role of autophagy in maintaining controlled and healthy cellular function.
Analysis of Autophagy Regulation: Discussion of Recent Research and New Technologies was organised by EuroSciCon. Further information is available online (
http://lifescienceevents.com).
DECEMBER 2013
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