Extra Reading for Protein Agg Flashcards
Describe the work of Komatsu et al. 2006
Through the use of mouse models and post-mortem analysis, they demonstrated that deletion of Atg7 (Autophagy related protein 7) lead to NDD, notably presented with behavioural and motor defects
Massive loss wasn’t specific to one particular region, demonstrating vulnerability in all neurons
Of note; polyubiquitinated proteins accumulated in autophagy-deficient neurons as inclusion bodies, which increased in size and number with ageing. There was, however, no obvious alteration in proteasome function.
What is the current view on lysosomes?
That they are not simply the terminal component for degradation, they contribute to macroautophagy through influencing both early and late steps, for example acting as a docking platform for mTOR and for AA sensing complexes.
Who is the master regulator for autophagy induction?
mammalian target of rapamycin kinase
Why are neurons so suscpetible to autophagy disruption?
Because neurons have unusually large expanses of dendritic and axonal cytoplasm they face particular hurdles in preventing dysfunctional organelles and cellular waste from accumulating over a lifetime without the aid of cell division, which mitotic cells can rely on to dilute these waste burdgens. Therefore, not surprisingly the neurons are particularly vulnerable to slowdowns in the proteolytic clearance of autolysosomal substrates
What does ULK stand for?
autophagy-related 2-Unc51-like kinase complex
What does the equilibreum between TORC1 inactivation and protein synthesis influence?
Synaptic plasticity, dendrite aboration and myelination
How does PD effect Autophagosome formation?
One effect of characteristically high intracellular -synuclein concentrations is inhibition of the GTPase Rab1A, believed to interfere with omegasome formation through Atg9 mislocalization
What did winslow et al. 2010 prove.
That omegosome formation is disrupted in PD thorugh the use of transgenic mice, mammalian cell cultures and Drosophila rhabdomere studies
Additionally they demonstrated that HD aggregation was worsened through injection of WT async, demonstrating a potentially greater than originally percieved effect on macroautophagy
–> Although they could not exclude that α-synuclein is also enhancing mutant huntingtin toxicity via autophagy-independent pathways, their cell biology data suggest that the effects on autophagy are significant contributors.
How does HD effect Autophagosome formation?
Mutant Htt binds to beclin-1 this prevents, or hinders the typically efficient process of membrane nucleation and elongation, thus preventing proper autphagosome formation or selection of susbtrate.
Addditionally in mouse models of HD they saw that macroautophagy was still occuring, yet autophagosomes were devoid of cargos.
What did Shibata et al. 2006 suggest?
Possibly the most intriguing theory as noted by Shibata and the lads, is that beclin-1 expression decreases in an age-dependent manner, from this finding they argue and the fact that beclin-1 act as haploinsufficient for autophagosome formation, they argue that this particular molecular phenotype encourages the age-dependent manner in which HD occurs
What are the effects of AD and ALS on autophagy?
Appears to be increased - potentially as a means of compensation?
What was the breakthrough paper by Filamenko et al. 2010
That autophagy is in fact selective, in subsets. e.g. Alfy receptor binds p62 positive cells.
Give examples of disrupted seleciton in NDD?
OPTN + p62 receptors - ALS
Pink1 and parkin, VP35 - PD, whilst async - binds abnormally tight to LAMP2a
Tau - AD - tau binds abnormally tight to LAMP2a
In mitophagy which proteins are recruited following membrane ubiquitination by parkin?
p62 LC3 and HDAC6
What two processes have NFkB signalling been implicated in?
Signalling has been activated by the presence of p62 inclusion bodies, AND TDP-43 positive inclusion bodies. Un ALS patients with either mutations in the gene encoding p62 or the OPTN gene encoding optineurin - On a molecular level, autophagy and NF-κB share common upstream signals and regulators and can control each other through positive or negative feedback loops, thus ensuring homeostatic responses. The connection between the two is intriguing and has yet to be completely explored.
