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

Laura Taylor Alto,Malú G Tansey,Isaac Treviño,Xi Chen,Kelly A Ruhn,Christopher Mark Norris

doi:10.1371/journal.pone.0096544

Laura Taylor Alto, Malú G Tansey + Show 4 more

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https://doi.org/10.1371/journal.pone.0096544

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Abstract

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.

Highlights

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansions in the huntingtin gene that result in an increased number of glutamine residues in the huntingtin protein
Chronic neuroinflammation is a characteristic feature of neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) [2,3] and recent data has established that inflammation is present in HD [4]
To provide rationale for an anti-inflammatory intervention to rescue medium spiny neurons (MSN), we first assessed the inflammatory profile of YAC128 transgenic (TG) compared to wild type (WT) mice using three independent approaches

Summary

Introduction

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansions in the huntingtin gene (htt) that result in an increased number of glutamine residues in the huntingtin protein (polyglutamine expansion). Inflammatory gene expression, including Tumor Necrosis Factor (TNF), is increased in brains of mutant htt carriers [9,10,11,12]. Inflammation is evident in the brain and peripheral blood in mouse models of HD that express mutant htt, including R6/2, YAC128 and HdhQ150/Q150 mice. These animal models have increased microglial density in the brain [16] and elevated expression of inflammation-related genes, including those related to TNF signaling pathways [10,17]

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