For decades the AD theory of accumulation of A beta plaques and phosphorylated tau tangles has dominated the research on AD. Notwithstanding the tremendous amount of exciting studies in the field, the progress to understand the cellular and molecular mechanisms underlying AD has not still yielded desirable treatment. Some researchers started to suspect that maybe there are other different or parallel unknown mechanisms to focus on in order to pinpoint the etiology of AD.
In this regard, a recent study has shown that the isomerization and epimerization of long-lived proteins prevent lysosomal degradation which result in the accumulation of dysfunctional lysosomes in neurons and lead to AD symptoms.
The team stated in their paper that: "Lysosomal failure caused by the iso/epi modifications documented to exist in both Aβ and Tau offers a direct connection between these observations and a potential new pathway to explore for the underlying cause and treatment of AD."
Article Spontaneous Isomerization of Long-Lived Proteins Provides a ...
Now, this discussion forum is open to opinions and arguments regarding this new hypothesis, and possibly a comparison of other rival hypotheses about mechanisms or etiology of AD.
This is a very challenging hypothesis that could be associated with various AD pathologies and can be used as the basis for further research in AD or other LSDs and if this hypothesis is correct, it would open up the possibility of treating or preventing other LSDs as well.
I think the starting point of this hypothesis was this paper :
https://www.nature.com/articles/s41598-018-21815-x
Understanding the extent of protein modification in normal and AD brain and its prospective association with aging is the next step.
This hypothesis has been around for quite a while. There is also a good body of evidence supporting the important role of lysosomes in the development of neurodegenerative disorders.
I guess all the proposed mechanisms are eventually interacting to lead to the pathogenesis of these disorders. There is no actual rivalry!
These hypotheses are not mutually exclusive. Already Alzheimer himself has speculated that not the plaques and tangles are the cause of AD, but soluble oligomers of the misfolded Aβ protein. The microscopically visible lesions would then be only correlates, but not cause, of the disease. Perhaps, they could be a waste dump, where afflicted cells put the misfolded proteins in a desperate attempt to reduce the damage done by them. The failure of plaque-reducing antibodies to prevent disease progression could certainly be interpreted that way.
The role of protein modification (spontaneous or enzymatic) in the misfolding and aggregation of proteins in amyloidoses is a very interesting issue, and addresses the pathomechanism one step earlier, but perhaps independently of the question of oligomer/aggregate.
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