Are the inclusions found in neurologic disease attempts at defense rather then the cause?

Thinking about pathologic changes in neurologic disease has been simplistic in the extreme.  Intially both senile plaques and neurofibrillary tangles were assumed to be causative for Alzheimer’s.  However there are 3 possible explanations for any microscopic change seen in any disease.  The first is that they are causative (the initial assumption).  The second is that they are a pile of spent bullets, which the neuron uses to defend itself against the real killer.  The third is they are tombstones, the final emanations of a dying cell.

A fascinating recent paper [ Neuron vol. 97 pp. 3 – 4, 108 – 124 ’18 ] http://www.cell.com/neuron/pdf/S0896-6273(17)31089-9.pdf gives strong evidence that some inclusions can be defensive rather than toxic.  It contains the following;

“In these studies, we found that formation of large inclusions was correlated with protection from a-synuclein toxicity”

The paper is likely to be a landmark because it ties two neurologic diseases (Parkinsonism and Alzheimer’s) together by showing that they may due to toxicity produced by single mechanism — inhibition of mitochondrial function.

Basically, the paper says that overproduction of alpha synuclein (the major component of the Lewy body inclusion of Parkinsonism) and tau (the major component of the neurofibrillary tangle of Alzheimer’s disease) produce death and destruction by interfering with mitochondria.  The mechanism is mislocalization of a protein called Drp1 which is important in mitochondrial function (it’s required for mitochondrial fission).

Actin isn’t just found in muscle, but is part of the cytoskeleton of every cell.  Alpha-synuclein is held to alter actin dynamics by binding to another protein called spectrin (which also binds to actin).  The net effect is to mislocalize Drp1 so it doesn’t bind to mitochondria where it is needed.  It isn’t clear to me from reading the paper, just where the Drp1 actually goes.

In any event overexpressing spectrin causes the alpha-synuclein to bind to it forming inclusions and protecting the cells.

There is a similar mechanism proposed for tau, and co-expressing alpha synuclein with Tau significantly enhances the toxicity of both models of tau toxicity which implies that they work by a common mechanism.

Grains of salt are required because the organism used for the model is the humble fruitfly (Drosophila).

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Comments

  • Ed Gehrman  On January 8, 2018 at 2:11 am

    I agree that Alzheimer’s is a defense, but against infection by Spiroplasma.
    Read a complete discussion of this situation at tseresearchcenter.org.
    We should think of Alzheimer’s as a TSE. How Alzheimer’s is transmitted is another question.
    Ed Gehrman

    • luysii  On January 8, 2018 at 11:16 pm

      Now that we know that each of us is really a community of organisms, most of which happily live in and on us causing no trouble, it becomes even harder to blame any of them for any neurologic (or systemic) disease.

  • DN  On January 8, 2018 at 4:16 am

    The Alzheimer’s prion hypotheses all have the same problem: there should be occasional cases at a young age, there should be clusters, and transplant recipients should be unusually likely to get early Alzheimer’s. This is not observed, to put it mildly. It appears to be a disease almost exclusive to old age, which suggests that it is a developmental state driven by genetics and endogenous hormones.

  • luysii  On January 8, 2018 at 11:21 pm

    Excellent point about transplants and Alzheimer’s. The early days of transplants were truly heroic and I completed my residency at the Denver VA where Tom Starzl was just getting started. The neurologic complications were incredible, fungal infections of the brain with extremely bizarre organisms due to the immunosuppressants used back then. I don’t think I ever saw one of his liver transplants leave the hospital. The kidney transplants did pretty well Presently, the guy across the street had a liver transplant 10 years ago.

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