HD Insights™

H D I N S I G H T S HD Insights, Vol. 10 4 Copyright © Huntington Study Group 2015. All rights reserved. Cicchetti, cont... H D I N S I G H T S CICCHETTI: …immunofluorescence, confocal and electron microscopy, Western immunoblotting, and infrared spectroscopy, to show that mHTT inclusions were indeed present in the transplanted tissue. This observation, which we were very excited about, raised a whole new set of questions. How did the mutant protein get to the transplanted tissue, which is genetically unrelated to the patient? In the paper, we proposed a series of non – cell-autonomous mechanisms to explain the propagation of mHTT. HD INSIGHTS: We know that mHTT will be produced within the neurons of individuals with HD. What role would transmission play in the disease and why is that important? CICCHETTI: This is a very important point. Because of the genetic nature of HD, the mutant protein is expressed ubiquitously, in every cell of the body. The extent to which non – cell-autonomous mechanisms of pathological protein spread may contribute to disease onset and development is unknown, but this observation alone may fundamentally change our understanding of the pathogenesis of HD, and of other neurodegenerative disorders. If non – cell-autonomous mechanisms do indeed play a significant role in disease pathophysiology, developing therapies that are designed to halt the propagation of mHTT will be of significant value. HD INSIGHTS: I'll return to the targets in a moment, but I wanted to touch on your mention of other diseases. Dr. Virginia Lee and her colleagues have described trans-synaptic transmission of α-synuclein in PD models. 2 Is there a common theme? CICCHETTI: Certainly. But besides the transsynaptic transmission of α-synuclein demonstrated in the original publication by Luk et al., 2 Lee's group also proposed the potential prion-like behavior of α-synuclein. 3 In HD, I do not personally believe that mHTT propagates in a prion-like fashion, that mHTT seeds pathology and changes the conformation of the protein in neighboring cells. However, I do believe in the trans-synaptic propagation of mHTT, something that we are currently working on. But what we are especially keen on is to explore the involvement of the immune system—blood-borne cells in particular—as a vehicle to transport and spread mHTT. HD INSIGHTS: So you think immune cells may be transporting mHTT? CICCHETTI: Other groups have already shown that monocytes, for example, express mHTT very early in the disease course. 4 As you pointed out, in HD patients, every cell of the body expresses mHTT, but certain cell types seem to be much more vulnerable to cell death, although the vulnerability of these cell populations is not well understood. So we know that peripheral cells express the mutant protein, and we now have evidence that there is leakage of the blood-brain barrier in HD patients, data that we will shortly submit for publication. Based on this, we believe that the transmigration of peripheral cells to the brain may be facilitated. I do think that that there is a strong possibility that mHTT spreads to the brain via blood-borne cells. HD INSIGHTS: Which immune cells do you think are involved? CICCHETTI: Based on current literature, 5 mHTT is detectable in monocytes and T cells, which specifically correlates with burden of disease scores, further suggesting that these populations could be used as biomarkers. Results from PET studies in HD patients also support the idea that microglial activation is an early event in HD pathogenesis. 6 There is strong evidence in favor of an inflammatory or immune-driven response that precedes neurodegeneration in HD. HD INSIGHTS: Do you think that these immune cells, which are facilitating the propagation of mHTT, are responsible for the spread of mHTT within the brain? CICCHETTI: I tend to believe so, but I'm not ruling out the possibility that there is a very high expression of mHTT first in the brain, and then we find residues of the protein in the periphery. However, my guess is that it is primarily the other way around, based on the fact that there are early signs of immune dysregulation, including elevated levels of cytokines in HD patients, 4 long before any of the neurological features that are used for diagnosis. Another avenue of propagation that we are currently exploring is that of exosomes and microvesicles, which can be released from peripheral cells. Their small size would allow them to enter the brain even in the absence of leakage of the blood-brain barrier. What is interesting about these small vesicles is that some of them contain mitochondria, which allows them to travel long distances because they have their own powerhouse. Despite their small size, they are big enough to carry various proteins, and could serve as miniature mHTT cargoes circulating from peripheral blood into the brain. HD INSIGHTS: Does this also suggest that peripheral markers could serve as biomarkers of HD? CICCHETTI: Absolutely, and a number of research groups have suggested this. Not only could they serve as biomarkers of HD, but also as markers of treatment efficacy. HD INSIGHTS: Have we seen any treatments that change these peripheral markers in HD? (continued on Page 12...)

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