AAV-dominant negative tumor necrosis factor (DN-TNF) gene transfer to the striatum does not rescue medium spiny neurons in the YAC128 mouse model of Huntington's disease.
CNS inflammation is a hallmark of neurodegenerative disease, and recent studies suggest that the inflammatory response may contribute to neuronal demise. In particular, increased tumor necrosis factor (TNF) signaling is implicated in the pathology of both Parkinson's disease (PD) and Alzheimer's disease (AD). We have previously shown that localized gene delivery of dominant negative TNF to the degenerating brain region can limit pathology in animal models of PD and AD. TNF is upregulated in Huntington's disease (HD), like in PD and AD, but it is unknown whether TNF signaling contributes to neuronal degeneration in HD. We used in vivo gene delivery to test whether selective reduction of soluble TNF signaling could attenuate medium spiny neuron (MSN) degeneration in the YAC128 transgenic (TG) mouse model of Huntington's disease (HD). AAV vectors encoding cDNA for dominant-negative tumor necrosis factor (DN-TNF) or GFP (control) were injected into the striatum of young adult wild type WT and YAC128 TG mice and achieved 30-50% target coverage. Expression of dominant negative TNF protein was confirmed immunohistologically and biochemically and was maintained as mice aged to one year, but declined significantly over time. However, the extent of striatal DN-TNF gene transfer achieved in our studies was not sufficient to achieve robust effects on neuroinflammation, rescue degenerating MSNs or improve motor function in treated mice. Our findings suggest that alternative drug delivery strategies should be explored to determine whether greater target coverage by DN-TNF protein might afford some level of neuroprotection against HD-like pathology and/or that soluble TNF signaling may not be the primary driver of striatal neuroinflammation and MSN loss in YAC128 TG mice.
Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Laura Taylor
LT
Alto
Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Xi
X
Chen
Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Kelly A
KA
Ruhn
Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Isaac
I
Treviño
Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America; Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Malú G
MG
Tansey
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009048:Motor Skills / Q000502:physiology; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology / Q000628:therapy; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D045442:Rotarod Performance Test; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha