Parkinson Disease: Tansey MG

Tansey MG, Frank-Cannon TC, McCoy MK, Lee JK, Martinez TN, McAlpine FE, Ruhn KA, Tran TA. · Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9040, USA. · Front Biosci. · Pubmed #17981581 No free full text.

Abstract: The inflammatory response in the brain associated with most chronic neurodegenerative diseases is termed neuroinflammation. Neuropathological and neuroradiological studies indicate that in certain neurodegenerative disorders neuroinflammation may be detectable years before significant loss of neurons occurs. In this review, we discuss the evidence from human studies and experimental models that implicate neuroinflammatory processes in the progressive neurodegeneration of the nigrostriatal pathway, the hallmark of Parkinson's Disease (PD). We discuss the neurotoxic role of microglia-derived inflammatory mediators which are suspected to hasten the death of nigral dopaminergic neurons, in particular the pro-inflammatory cytokine Tumor Necrosis Factor (TNF) and its downstream signaling pathways. We also entertain the possibility that chronic microglia activation links proteinopathies to neurodegeneration. The rationale for current and future use of anti-inflammatory approaches to protect vulnerable neuronal populations in PD is also reviewed.

Tansey MG, McCoy MK, Frank-Cannon TC. · Department of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA. · Exp Neurol. · Pubmed #17720159 No free full text.

Abstract: Most acute and chronic neurodegenerative conditions are accompanied by neuroinflammation; yet the exact nature of the inflammatory processes and whether they modify disease progression is not well understood. In this review, we discuss the key epidemiological, clinical, and experimental evidence implicating inflammatory processes in the progressive degeneration of the dopaminergic (DA) nigrostriatal pathway and their potential contribution to the pathophysiology of Parkinson's disease (PD). Given that interplay between genetics and environment are likely to contribute to risk for development of idiopathic PD, recent data showing interactions between products of genes linked to heritable PD that function to protect DA neurons against oxidative or proteolytic stress and inflammation pathways will be discussed. Cellular mechanisms activated or enhanced by inflammatory processes that may contribute to mitochondrial dysfunction, oxidative stress, or apoptosis of dopaminergic (DA) neurons will be reviewed, with special emphasis on tumor necrosis factor (TNF) and interleukin-1-beta (IL-1beta) signaling pathways. Epigenetic factors which have the potential to trigger neuroinflammation, including environmental exposures and age-associated chronic inflammatory conditions, will be discussed as possible 'second-hit' triggers that may affect disease onset or progression of idiopathic PD. If inflammatory processes have an active role in nigrostriatal pathway degeneration, then evidence should exist to indicate that such processes begin in the early stages of disease and that they contribute to neuronal dysfunction and/or hasten neurodegeneration of the nigrostriatal pathway. Therapeutically, if anti-inflammatory interventions can be shown to rescue nigral DA neurons from degeneration and lower PD risk, then timely use of anti-inflammatory therapies should be investigated further in well-designed clinical trials for their ability to prevent or delay the progressive loss of nigral DA neurons in genetically susceptible populations.

McCoy MK, Ruhn KA, Martinez TN, McAlpine FE, Blesch A, Tansey MG. · Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. · Mol Ther. · Pubmed #18628756 No free full text.

Abstract: Neuroinflammatory processes have been implicated in the progressive loss of ventral midbrain dopaminergic (DA) neurons that give rise to Parkinson's disease (PD), a late-onset movement disorder that affects 2% of the population over the age of 70 years. We have shown earlier, in two rat models of PD, that inhibition of the proinflammatory cytokine tumor necrosis factor (TNF) through nigral infusion of dominant-negative (DN-TNF) protein (XENP345) attenuates DA neuron loss. The objectives of this study were to develop a constitutive lentiviral vector encoding dominate-negative TNF, and to determine whether a gene therapy approach to deliver DN-TNF directly into the rodent substantia nigra could prevent or attenuate neurotoxin-induced DA neuron loss and associated behavioral deficits. Here we demonstrate that a single injection of lentivirus-expressing DN-TNF into rat substantia nigra, administered concomitant with a striatal 6-hydroxydopamine lesion, results in sufficiently high expression of inhibitor in vivo to attenuate both DA neuron loss and behavioral deficits resulting from striatal dopamine depletion. Our findings demonstrate the feasibility and efficacy of dominant-negative TNF gene transfer as a novel neuroprotective strategy to prevent or delay nigrostriatal pathway degeneration. This strategy holds the potential for therapeutic application in the treatment of PD.

McCoy MK, Martinez TN, Ruhn KA, Wrage PC, Keefer EW, Botterman BR, Tansey KE, Tansey MG. · Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. · Exp Neurol. · Pubmed #18061169 links to  free full text

Abstract: Adult adipose contains stromal progenitor cells with neurogenic potential. However, the stability of neuronal phenotypes adopted by Adipose-Derived Adult Stromal (ADAS) cells and whether terminal neuronal differentiation is required for their consideration as alternatives in cell replacement strategies to treat neurological disorders is largely unknown. We investigated whether in vitro neural induction of ADAS cells determined their ability to neuroprotect or restore function in a lesioned dopaminergic pathway. In vitro-expanded naïve or differentiated ADAS cells were autologously transplanted into substantia nigra 1 week after an intrastriatal 6-hydroxydopamine injection. Neurochemical and behavioral measures demonstrated neuroprotective effects of both ADAS grafts against 6-hydroxydopamine-induced dopaminergic neuron death, suggesting that pre-transplantation differentiation of the cells does not determine their ability to survive or neuroprotect in vivo. Therefore, we investigated whether equivalent protection by naïve and neurally-induced ADAS grafts resulted from robust in situ differentiation of both graft types into dopaminergic fates. Immunohistological analyses revealed that ADAS cells did not adopt dopaminergic cell fates in situ, consistent with the limited ability of these cells to undergo terminal differentiation into electrically active neurons in vitro. Moreover, re-exposure of neurally-differentiated ADAS cells to serum-containing medium in vitro confirmed ADAS cell phenotypic instability (plasticity). Lastly, given that gene expression analyses of in vitro-expanded ADAS cells revealed that both naïve and differentiated ADAS cells express potent dopaminergic survival factors, ADAS transplants may have exerted neuroprotective effects by production of trophic factors at the lesion site. ADAS cells may be ideal for ex vivo gene transfer therapies in Parkinson's disease treatment.