Growing up in a seaside town in the 1980s led to me spending a lot of my “formative years” in the local amusement arcades, playing iconic video games like Space Invaders (at which I was average) and Asteroids (I was the kid to beat!). One game I never got the hang of was Pac Man, where you had to guide a munching yellow ball around a maze eating up lots of dots. I even bought a book ‘Mastering Pac Man’ which didn’t help much – I was just plain rubbish!
Dr Brian Dickie and Pac Man
Talking about rubbish, fast forward 30 years and Prof Anne Simondsen from The University of Oslo is on the platform in Chicago describing the ways in which neurones deal with their cellular rubbish, such as poorly manufactured or damaged proteins.
Much as the dots are gobbled up by Pac Man, so cells employ a couple of basic ways to dispose of and recycle damaged proteins. One is a process called proteasomal degradation, which has been discussed on this website before by one of our guest bloggers, Prof John Mayer. However, some proteins, especially protein aggregates, are a bit too large and tough to be broken down by the proteasome, but they can be degraded by another process called autophagy – which can literally be translated as ‘self-eating’.
Prof Simondsen explained how aggregated proteins and even larger cellular structures can be packaged up for destruction by being encapsulated within membranes, forming structures called autophagosomes. These in turn seek out a structure called the lysosome, which contains digestive enzymes which break down the protein rubbish and keep the cell ‘spick and span’.
Using studies involving fruit fly models (a favourite model for cell biologists) she showed that the autophagy process declines with age, which is unfortunate because protein damage tends to increase with age. It was therefore no surprise that the level of autophagy in the brain was directly associated with the accumulation of protein ‘inclusions’, the health of neurones and the life expectancy of the flies.
Much of the evidence supporting a role for autophagy in neurodegeneration comes from the field of Huntington’s disease. Prof Simondsen explained how a particular mutated protein – called huntingdin – accumulates in the dying neurones and is a classic pathological hallmark of the disease. She demonstrated that autophagy normally plays a central role in the disposal of damaged huntingdin, but the system simply cannot cope with the amount of damaged protein, which starts to accumulate and literally ‘gunge up’ the cell. However, by stimulating the manufacture of additional autophagy machinery, the amount of aggregated protein can be reduced, helping to protect the neurones. This has so far only been shown in simple lab models of Huntington’s disease, but the encouraging results mean that further development to try and develop a treatment is underway.
So, could a similar approach be useful in other neurodegenerative diseases such as MND? Certainly, for some types of MND, such as those linked to a rare gene mutation called CHMP2B, it appears that a component of the autophagic machinery is impaired, which leads to protein build-up in cell models.
Dr Eiichi Tokada (Umea University, Sweden) provided further evidence that autophagy plays a role in disease progression in the SOD1 form of MND. By switching off a crucial component of the autophagy machinery, the disease progression in SOD1 mice was accelerated and their lifespan shortened. In addition, when he examined the spinal cords of the mice, he saw an increased presence of the characteristic SOD1 protein aggregates – a pathological hallmark of the disease.
Dr Faisal Fecto (Northwestern University, USA) provided evidence from a third genetic cause of MND. He showed how mutations in the Ubiquilin 2 gene disrupt the autophagy pathway by stopping the autophagosomes from linking up with the lysosomes.
So, it certainly seems that autophagy has a role to play in some of the rarer familial froms of MND. It remains to be seen to what extent it is involved in MND more generally, but it may mean that the potential treatment strategies being developed for Huntington’s disease may offer future opportunities for MND as well.
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