Cancer research will only progress meaningfully towards control of all cancer when the research community puts significant time and effort into finding common mechanisms shared by many or all cancers - or better still, attacking the one known mechanism shared by all cancers, which is abuse of telomere lengthening. The reason that the cancer community struggles with progress is that there are hundreds of forms of cancer, and researchers largely continue to try to address them one by one. There is a lot of cancer, but only so much funding and only so many scientists. A better way forward is needed. The question for today, however, is whether or not this principle of action extends to another broad class of widely varied conditions, the neurodegenerative diseases that corrode the aging brain. Are there faster paths forward here as well, built on common mechanisms? I'm on the fence on this topic. I think it easy to argue that any two different forms of neurodegeneration are far more distinct from one another than any two types of cancer; they involve completely different ways to disrupt cellular activity in the brain or kill brain cells. There is no one mechanism with a clear analogy to the central role of abuse of telomere lengthening in cancer when it comes to neurodegenerative disease.
Still, it is tempting to speculate on mechanisms that might be shared between many different types of neurodegenerative disease, because if they do exist, that offers the same prospect of faster progress, if only the research community better directed its efforts. Obviously, at root, many layers of cause and consequence removed from the disease state, we can look to the forms of tissue and cell damage outlined in the SENS rejuvenation research proposals - the root causes of aging. Most neurodegeration is age-related because it is caused by aging, and thus the first resort should probably be attempts at first principles rejuvenation, therapies based on repair of root cause damage. Sadly, few in the research community agree with that statement; persuading them to see the light is an ongoing project. Further along the chain of damage and dysfunction can be found other examples. We might, for example, consider the failure of cerebral spinal fluid drainage channels as a possible common factor in all conditions involving the build-up of aggregates and other unwanted molecular waste in the brain. Equally, there may be other, more esoteric points at which intervention is possible, though in general the later in the disease process the intervention occurs, the less likely it is to produce more than marginal benefits, if the past century of medicine is any guide to what the future holds. You might look at this work as an example of the type:
Abnormal proteins found in Alzheimer's disease, Parkinson's disease, and Huntington's disease all share a similar ability to cause damage when they invade brain cells. The finding potentially could explain the mechanism by which Alzheimer's, Parkinson's, Huntington's, and other neurodegenerative diseases spread within the brain and disrupt normal brain functions. The finding also suggests that an effective treatment for one neurodegenerative disease might work for other neurodegenerative diseases as well. "A possible therapy would involve boosting a brain cell's ability to degrade a clump of proteins and damaged vesicles. If we could do this in one disease, it's a good bet the therapy would be effective in the other two diseases."
Previous research has suggested that in all three diseases, proteins that are folded abnormally form clumps inside brain cells. These clumps spread from cell to cell, eventually leading to cell deaths. Different proteins are implicated in each disease: tau in Alzheimer's, alpha-synuclein in Parkinson's and huntingtin in Huntington's disease. The new study focused on how these misfolded protein clumps invade a healthy brain cell. The authors observed that once proteins get inside the cell, they enter vesicles (small compartments that are encased in membranes). The proteins damage or rupture the vesicle membranes, allowing the proteins to then invade the cytoplasm and cause additional dysfunction. When protein clumps invade vesicles the cell gathers the ruptured vesicles and protein clumps together so the vesicles and proteins can be destroyed. However, the proteins are resistant to degradation. "The cell's attempt to degrade the proteins is somewhat like a stomach trying to digest a clump of nails."
Numerous pathological amyloid proteins spread from cell to cell during neurodegenerative disease, facilitating the propagation of cellular pathology and disease progression. Understanding the mechanism by which disease-associated amyloid protein assemblies enter target cells and induce cellular dysfunction is, therefore, key to understanding the progressive nature of such neurodegenerative diseases. In this study, we utilized an imaging-based assay to monitor the ability of disease-associated amyloid assemblies to rupture intracellular vesicles following endocytosis. We observe that the ability to induce vesicle rupture is a common feature of α-synuclein (α-syn) assemblies, as assemblies derived from wild type (WT) or familial disease-associated mutant α-syn all exhibited the ability to induce vesicle rupture. Similarly, different conformational strains of WT α-syn assemblies, but not monomeric or oligomeric forms, efficiently induced vesicle rupture following endocytosis.
The ability to induce vesicle rupture was not specific to α-syn, as amyloid assemblies of tau and huntingtin Exon1 with pathologic polyglutamine repeats also exhibited the ability to induce vesicle rupture. We also observe that vesicles ruptured by α-syn are positive for the autophagic marker LC3 and can accumulate and fuse into large, intracellular structures resembling Lewy bodies in vitro. Finally, we show that the same markers of vesicle rupture surround Lewy bodies in brain sections from PD patients. These data underscore the importance of this conserved endocytic vesicle rupture event as a damaging mechanism of cellular invasion by amyloid assemblies of multiple neurodegenerative disease-associated proteins, and suggest that proteinaceous inclusions such as Lewy bodies form as a consequence of continued fusion of autophagic vesicles in cells unable to degrade ruptured vesicles and their amyloid contents.