These are my notes from week 7 of Harvard’s Neurobiology 305qc course “Biochemistry and Biology of Neurodegenerative Diseases”, held by Michael Wolfe and Dominic Walsh on December 15, 2014.

For this class, we read four review/commentary pieces with differing perspectives. In one corner, Stanley Prusiner and Mathias Jucker both argue that all neurodegenerative diseases are caused by prions [Prusiner 2012, Jucker & Walker 2013]. Chris Dobson and colleagues take just a slightly different angle, focusing more on solubility and proteostasis [Vendruscolo 2011]. Then, for something entirely different, Ralph Nixon proposes that neurodegenerative diseases are united by defects in autophagy [Nixon 2013].

We started with the question of what unites all of the proteins involved in neurodegenerative disorders which we’ve discussed in this class. Whether the proteins involved in these diseases should be called “prions” is a topic sure to incite controversy, and this class meeting was no exception. I didn’t take many notes on that debate.

All of the proteins discussed in this class are found in deposits in affected patients, and most (all?) of them can form aggregates that meet the functional definition of amyloid - congophilicity and fibrillar appearance. Chris Dobson has pointed out that essentially any protein - even highly soluble proteins like myoglobin [Fandrich 2001] - can form amyloid at the right pH and the right salt concentration. But that doesn’t mean they will do so in any realistic conditions in vivo, whereas the key proteins in neurodegenerative disease do form these sorts of aggregates in vivo.

We don’t have a full picture of the mechanisms by which any of these aggregates are neurotoxic - even for PrP. Yet some people have claimed that these diseases share not only a unifying mechanism of etiology, but also a unifying mechanism of neurotoxicity. For instance, [Nixon 2013] proposes that defects in autophagy are drivers of pathology in all of these diseases.

The ubiquitin-proteasome system may be impaired in some or all of these diseases. UBQLN2 is an ALS gene that encodes a protein involved in the ubiquitin-proteasome system. PARK2 is a Parkinson’s gene that encodes a E3 ubiquitin ligase. The beauty of genetics is that correlation does imply causation, so these examples demonstrate that disruptions of the ubiquitin-proteasome system can cause some of these disorders. This doesn’t tell us much about whether ubiquitin-proteasome system disruptions are responsible for any sporadic cases. Protein aggregates in many of these diseases - Lewy bodies, Tau deposits, and TDP-43 deposits - were originally identified as being ubiquitin-positive, and the core protein was not characterized until later. This, too, doesn’t really tell us where ubiquitination lies in the chain of causality. In PrP disease, there is pretty good evidence that some amount of ubiquitin-proteasome system disruption does occur downstream of prion infection [Kristiansen 2007], but whether or not any such disruptions may occur upstream of sporadic prion disease is unknown.

You can make an argument for a number of proteins or pathways relating to autophagy being disrupted in neurodegenerative diseases, however, some of these are a bit stretched. For instance, [Nixon 2013] discusses presenilin 1 being required for lysosome acidification, and although that may be true, presenilin 1 has a much more obvious role in Alzheimer’s as a component of gamma secretase responsible for generating Aβ. Similarly, the review mentions the APOE E4 allele disrupting membrane integrity even though most people think it is more clearly implicated in Aβ clearance, and SQSTM1 (p62) mutations being involved in ALS even though when I looked up this gene I found that OMIM #601530 talks exclusively about Paget’s disease of bone. Altogether it starts to seem like it takes some cherry-picking to argue for a very central role of autophagy in neurodegeneration, though of course it is very likely involved to some degree.

Why are neurons so sensitive, even when the proteins involved in these diseases are expressed in so many other cells? Here are a few ideas. They’re post-mitotic, and they have a fragile morphology with long, thin processes extending far from the nucleus. Transcription occurs in these processes, distal to the cell body. They’re interconnected and have electrophysiological activity, and are plastic in that they have dynamic remodeling of spines.