2010 Dead Sea, Israel: ISF-Legacy Meeting Part I

An auspicious conference was held recently in Ein Bokek, Israel, jointly organized by the Israel Science Foundation (ISF) and the Legacy Heritage Fund.  This meeting of the minds brought together an international group of scientists from a wide variety of fields to discuss "New Approaches to Neurodegenerative Diseases." The ALS Forum is pleased to bring you coverage of several of the key ALS stories presented throughout the meeting.

Theme I: Getting rid of misfolded proteins

Accumulation of misfolded proteins causes havoc in ALS and several neurodegenerative disease models, overwhelming the cell’s normal degradative pathways and leading to cellular toxicity.  Autophagy and the ubiquitin proteosome system (UPS) are the two main mechanisms by which a cell disposes of unwanted misfolded proteins.

In autophagy, cytoplasmic waste is collected and ultimately degraded by the lysosomal machinery.  While the route to the lysosome differs between the three types of autophagy, the destination is the same.  In chaperone-mediated autophagy, specific substrates are recognized by chaperone proteins and delivered to the lysosomal lumen by receptor-mediate translocation.  In contrast, microautophagy involves direct lysosomal engulfment of cytoplasmic contents.  The third type involves autophagosome vesicles, which trap cytoplasmic components and fuse with the lysosomal membrane.  This last type – macroautophagy – was the focus of a talk by David Rubinsztein of the Cambridge Institute of Medical Research, UK, and for convenience hereafter is referred to as autophagy. 

Rubinsztein presented mounting evidence indicating that enhancing autophagy is an efficacious therapeutic approach to treat neurodegenerative disease.  Rubinsztein and colleagues previously showed (Nat Genetics, 2004) that increasing autophagy with the rapamycin analog, CCI-779, reduced accumulation of mutant huntingtin protein and improved motor performance in the R6/2 model of Huntington’s Disease.  Subsequent work showed that the protective effects of enhancing autophagy were not limited to expanded polyglutamine repeat-containing proteins but extended to other aggregate-prone proteins implicated in neurodegenerative diseases, such as alpha-synuclein, ataxin-3, and tau. 

While rapamycin acts on mTOR (mammalian Target Of Rapamycin) to increase autophagy, this process can also be increased by an mTOR-independent pathway.   In a later study, Rubinsztein and Stuart Schreiber, of the Broad Institute of Harvard and MIT, collaborated to identify small molecule modulators of autophagy in a screen performed in yeast (Nat Chem Biol, 2007).  They identified three novel small molecule enhancers of autophagy that cleared mutant huntingtin and alpha-synuclein proteins independently of the mTOR pathway.  This mTOR-independent pathway is thought to be regulated by intracellular calcium and cAMP levels and can be activated by drugs such as lithium and valproate (drugs already being tested for ALS and other neurodegenerative diseases).

The protective effects of autophagy may not only be due to the increased clearance of aggregated protein, as Rubinsztein explained in his presentation.  Autophagy may also exert an anti-apoptotic effect by enhancing clearance of intact, as well as damaged mitochondria.  Because fewer mitochondria would be available to release cytochrome c and trigger downstream activation of caspase-9, the mitochondrial mediated apoptotic pathways normally activated in disease would be dampened.  

Rubinsztein drew further attention to the potential cross-talk between the two pathways, mentioning that the anti-apoptotic proteins Bcl2 and Bcl-XL have also been shown to inhibit autophagy.  Additional work is needed to better understand the multimodal effects of autophagy and its relationship with cell survival and cell death pathways.

Recent work from Rubinsztein and colleagues published in the February 2010 issue of PloS revealed a novel connection between autophagy and the huntingtin protein.  They showed that expression of wildtype huntingtin protein with a deleted stretch of seven glutamines (deltaQ-htt) could improve motor function and increase survival in the HD mouse model expressing the expanded repeat 140Q-htt mutant protein.  Reduced levels of aggregated huntingtin protein and upregulation of the autophagy marker, microtubule-associated protein 1 light chain 3-II, suggested that the protective effects of deltaQ-htt were mediated by enhancing autophagy.  Intriguingly, they found that two downstream targets of the mTOR pathway were not activated by the expression of the deltaQ-htt protein, indicating that autophagy was occurring via an mTOR-independent pathway.

Rubinsztein and colleagues then went on to show that expression of deltaQ-htt in wildtype mice increased longevity by almost twenty percent.  This study supports the hypothesis that enhancing autophagy can protect mammals from the normal aging process, which is characterized by age-related decline in lysosomal function and accumulation of misfolded proteins.  These results fit well with previous observations in flies and worms showing autophagy regulates lifespan extension.  

Collectively, these studies highlight the potential therapeutic value of enhancing autophagy to treat neurodegenerative disease, as well as to delay the normal aging process.  With special regard to ALS therapeutic development, this approach offers a double hit on two critical pathologies associated with disease progression – accumulation of damaged mitochondria and of toxic misfolded proteins – and offers to be a promising area of further exploration.   

Menzies, PhD, Scientific Program Officer at Prize4Life


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