HD Insights™

Inhibition of mitochondrial protein import by mutant huntingtin Nat Neurosci. 2014 Jun;17(6):822-31. doi: 10.1038/nn.3721. Epub 2014 May 18. By: Yano H, Baranov SV, Baranova OV, Kim J, Pan Y, Yablonska S, Carlisle DL, Ferrante RJ, Kim AH, Friedlander RM. (Summary by Lise Munsie, PhD) Most influential paper In the clinic… Copyright © Huntington Study Group 2014. All rights reserved. Research Round-Up: Insights, cont... Mutant huntingtin is present in neuronal grafts in Huntington's disease patients Ann Neurol. 2014 Jul;76(1):31-42. doi: 10.1002/ana.24174. Epub 2014 Jun 6. By: Cicchetti F, Lacroix S, Cisbani G, Vallières N, Saint-Pierre M, St-Amour I, Tolouei R, Skepper JN, Hauser RA, Mantovani D, Barker RA, Freeman TB (Summary by Francesca Cicchetti, PhD) Mutant huntingtin (mHTT), which drives HD pathology, has long been thought to exert its effects in a cell-autonomous manner, where degeneration occurs within individual cells that carry the mutant gene. We investigated the hypothesis that mHTT is capable of spreading within cerebral tissue. The brains of four HD patients who received genetically unrelated fetal neural allografts at least a decade earlier were examined postmortem. We found a number of mHTT protein aggregates located within intracerebral allografts of striatal tissue in three of these HD patients. No grafts survived in the fourth transplant recipient. The mHTT aggregates were observed in the extracellular matrix of the genetically unrelated transplanted tissue, while in the host brain they were localized in neurons, neuropil, extracellular matrix, and blood vessels. In addition, peripheral immune cells in separate HD patients contained mHTT. There are thus a number of non-cell autonomous mechanisms that could explain these observations, including trans-synaptic propagation and hematogenous transport of mHTT, among others. This is the first in vivo demonstration of mHTT spread in patients with a monogenic neurodegenerative disorder of the CNS. These observations raise questions about the importance of non–cell-autonomous mechanisms of pathological protein spread, and provide new targets for the development of therapeutic strategies. Image: A. Double immunohistochemical staining for the neuronal marker NeuN (revealed with the chromogen DAB - brown color) and EM48 (that stains for mHTT aggregates, revealed with nickel intensified DAB – black color) in the cortex of an HD grafted case. mHTT aggregates were often observed aligning in a linear array, seemingly following the pattern of a dendritic segment. Image: B. Schematic of how mHTT in layer V of the host cortex may spread trans-synaptically to the striatum and graft. Mitochondrial dysfunction is intimately involved in the progression of HD; however, the mechanism of this dysfunction is unknown. Robert Friedlander's group explored this in a recent Nature Neuroscience paper. Initially, the authors found that mHTT is specifically localized to mitochondria in brains from HD patients and also mouse models. Unbiased protein identification from immunoprecipitation shows that mHTT binds members of the TIM23 complex, a complex that imports matrix proteins into the inner mitochondrial membrane. Using in vitro mitochondrial protein assays, the group demonstrated that the N-terminus of mHTT is involved in this aberrant binding, leading to decreased mitochondrial protein import. This defect is enhanced in mitochondria purified from synaptosomes, compared to mitochondria purified from other parts of the cell or other cell types. The group showed that the mitochondrial protein import dysfunction is an mHTT- specific function and not mediated through the polyglutamine expansion alone, and thus is a mechanism specific to HD. They additionally showed that altering protein import to the mitochondria is neurotoxic and that overexpressing major subunits of the TIM23 complex can rescue mHTT-induced neurotoxicity. H D I N S I G H T S HD Insights, Vol. 9 5

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