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Academic technology transfer in its current form began with the passage of the Bayh–Dole Act in 1980, which allowed universities to retain ownership of federally funded intellectual property. Since that time, a profession has evolved that has transformed how inventions arising in universities are treated, resulting in significant impact to US society. While there have been a number of articles highlighting benefits of technology transfer, now, more than at any other time since the Bayh–Dole Act was passed, the profession and the impacts of this groundbreaking legislation have come under intense scrutiny. This article serves as an examination of the many positive benefits and evolution, both financial and intrinsic, provided by academic invention and technology transfer, summarized in Table 1. Table 1 Summary Table of the Benefits of Academic Technology Transfer Keywords: Technology transfer, Innovation, Bayh–Dole, Commercialization, Start-ups, Technology licensing, Academic innovation INTRODUCTION Technology transfer is defined as “the process of transferring scientific findings from one organization to another for the purpose of further development and commercialization” by the Association of University of Technology Managers (AUTM). This process typically includes sifting for gold (identifying new technology) and knowing what to do with it when you find it (strategies for protection through patents and copyrights, the development of commercialization strategies such as technology development, marketing, and licensing to existing private companies, or the creation of new start-up companies based on the technology) (11).

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mice and nonhuman primates causes a parkinsonian disorder characterized by a loss of dopamine-producing neurons in the substantia nigra and corresponding motor deficits. MPTP has been proposed to exert its neurotoxic effects through a variety of mechanisms, including inhibition of complex I of the mitochondrial respiratory chain, displacement of dopamine from vesicular stores, and formation of reactive oxygen species from mitochondrial or cytosolic sources. However, the mechanism of MPTP-induced neurotoxicity is still a matter of debate. Recently, we reported that the yeast single-subunit nicotinamide adenine dinucleotide (reduced) dehydrogenase (NDI1) is resistant to rotenone, a complex I inhibitor that produces a parkinsonian syndrome in rats, and that overexpression of NDI1 in SK-N-MC cells prevents the toxicity of rotenone. In this study, we used viral-mediated overexpression of NDI1 in SK-N-MC cells and animals to determine the relative contribution of complex I inhibition in the toxicity of MPTP. In cell culture, NDI1 overexpression abolished the toxicity of 1-methyl-4-phenylpyridinium, the active metabolite of MPTP. Overexpression of NDI1 through stereotactic administration of a viral vector harboring the NDI1 gene into the substantia nigra protected mice from both the neurochemical and behavioral deficits elicited by MPTP. These data identify inhibition of complex I as a requirement for dopaminergic neurodegeneration and subsequent behavioral deficits produced by MPTP. Furthermore, combined with reports of a complex I defect in Parkinson's disease (PD) patients, the present study affirms the utility of MPTP in understanding the molecular mechanisms underlying dopaminergic neurodegeneration in PD.

Sporadic Parkinson's disease (PD) is most likely caused by a combination of environmental exposures and genetic susceptibilities, although there are rare monogenic forms of the disease. Mitochondrial impairment at complex I, oxidative stress, alpha-synuclein aggregation, and dysfunctional protein degradation, have been implicated in PD pathogenesis, but how they are related to each other is unclear. To further evaluated PD pathogenesis here, we used in vivo and in vitro models of chronic low-grade complex I inhibition with the pesticide rotenone. Chronic rotenone exposure in vivo caused oxidative modification of DJ-1, accumulation of alpha-synuclein, and proteasomal impairment. Interestingly, the effects become more regionally restricted such that systemic complex I inhibition eventually results in highly selective degeneration of the nigrostriatal pathway. DJ-1 modifications, alpha-synuclein accumulation, and proteasomal dysfunction were also seen in vitro and these effects could be prevented with alpha-tocopherol. Thus, chronic exposure to a pesticide and mitochondrial toxin brings into play three systems, DJ-1, alpha-synuclein, and the ubiquitin-proteasome system, and implies that mitochondrial dysfunction and oxidative stress link environmental and genetic forms of the disease.

Parkinson's disease (PD) is a progressive neurological disorder marked by nigrostriatal dopaminergic degeneration and development of cytoplasmic proteinaceous aggregates known as Lewy bodies. Although the pathogenic mechanisms responsible for PD are not completely understood, many clues have come from biochemical, epidemiological, and genetic studies. Mutations in certain genes found in rare, familial cases of PD, such as alpha-synuclein and parkin, suggest a role for the ubiquitin-proteosome system and aberrant protein aggregation. Biochemical analyses have implicated mitochondrial dysfunction in PD. Epidemiological and animal model studies point to a role for environmental toxins, some of which are mitochondrial inhibitors. Mitochondrial dysfunction, resulting from either genetic defects, environmental exposures or an interaction between the two, may cause alpha-synuclein aggregation or neurodegeneration through oxidative stress or excitotoxicity. A better understanding of the mechanisms underlying PD should reveal novel therapeutic targets.

Chronic infusion of rotenone (Rot) to Lewis rats reproduces many features of Parkinson disease. Rot (3 mg/kg/day) was infused subcutaneously to male Lewis rats for 6 days using Alzet minipumps. Control rats received the vehicle only. Presence of 0.1% bovine serum albumin during the isolation procedure completely removed rotenone bound to the mitochondria. Therefore all functional changes observed were aftereffects of rotenone toxicity in vivo. In Rot rat brain mitochondria (Rot-RBM) there was a 30-40% inhibition of respiration in State 3 and State 3U with Complex I (Co-I) substrates and succinate. Rot did not affect the State 4Δψ of RBM and rat liver mitochondria (RLM). However, Rot-RBM required two times less Ca2+ to initiate permeability transition (mPT). There was a 2-fold increase in or H2O2 generation in Rot-RBM oxidizing glutamate. Rot infusion affected RLM little. Our results show that in RBM, the major site of reactive oxygen species generation with glutamate or succinate is Co-I. We also found that Co-II generates substantial amounts of reactive oxygen species that increased 2-fold in the Rot-RBM. Our data suggest that the primary mechanism of the Rot toxic effect on RBM consists in a significant increase of generation that causes damage to Co-I and Co-II, presumably at the level of 4Fe-4S clusters. Decreased respiratory activity diminishes resistance of RBM to Ca2+ and thus increases probability of mPT and apoptotic cell death. We suggest that the damage to Co-I and Co-II shifts generation from the CoQ10 sites to more proximal sites, such as flavines, and makes it independent of the RBM functional state.

Paraquat, MPTP, and rotenone reproduce features of Parkinson's disease (PD) in experimental animals. The exact mechanisms by which these compounds damage the dopamine system are not firmly established, but selective damage to dopamine neurons and inhibition of complex I are thought to be involved. We and others have previously documented that the toxic metabolite of MPTP, MPP+, is transported into dopamine neurons through the dopamine transporter (DAT), while rotenone is not transported by DAT. We have also demonstrated the requirement for complex I inhibition and oxidative damage in the dopaminergic neurodegeneration produced by rotenone. Based on structural similarity to MPP+, it has been proposed that paraquat exerts selective dopaminergic toxicity through transport by the DAT and subsequent inhibition of mitochondrial complex I. In this study we report that paraquat is neither a substrate nor inhibitor of DAT. We also demonstrate that in vivo exposure to MPTP and rotenone, but not paraquat, inhibits binding of 3H-dihydrorotenone to complex I in brain mitochondria. Rotenone and MPP+ were both effective inhibitors of complex I activity in isolated brain mitochondria, while paraquat exhibited weak inhibitory effects only at millimolar concentrations. These data indicate that, despite the apparent structural similarity to MPP+, paraquat exerts its deleterious effects on dopamine neurons in a manner that is unique from rotenone and MPTP.

Recent epidemiological studies have shown that hypertensive men are more likely to undergo surgical intervention for irritative voiding symptoms from BPH than age-matched controls. Indeed, noradrenergic nerves which regulate vascular tone also participate in the functional component of bladder outlet obstruction due to BPH. Newer, less invasive therapies for BPH such as thermal therapy can relieve symptoms yet do not eliminate obstruction based on urodynamic studies. Coincidentally, drugs such as alpha-adrenoceptor antagonists, which have been thought to relieve obstruction due to a peripheral effect, can be given intrathecally in animals to relieve urinary frequency due to obstruction. Taken together these observations implicate both peripheral and central sympathetic pathways in the motor control of the urinary bladder especially with disease states. We have used the hypertensive and behaviourally hyperactive spontaneously hypertensive rat (SHR), to investigate the roles sympathetic pathways or micturition. Elevated nerve growth factor (NGF) derived from vascular and bladder smooth muscle cells of the SHR appears to direct morphological, biochemical, and functional changes. The increase in NGF can apparently be explained by stabilization of its mRNA leading to increased synthesis in NGF. Bladders from SHRs develop a profuse noradrenergic hyperinnervation compared with the control WKY strain. Since afferents supplying the SHR bladder are hypertrophied, changes in afferent pathways are also likely. These differences in innervation and NGF in the SHR may explain changes in function. SHRs void 3 times as frequently as their genetic controls. Urinary frequency can be reduced by alpha-adrenoceptor antagonists. Cystometrograms performed in SHRs reveal lower bladder capacities and micturition volumes and the presence of unstable contractions compared with the WKY rat. Intrathecal, rather than intra-arterial administration of the alpha-adrenoceptor antagonist doxazosin reduces unstable contractions in the SHR. In vitro muscle bath studies have shown enhanced responses of SHR bladder smooth muscle to alpha-adrenoceptor agonists. It is likely that upregulation of NGF production causes sensory and possibly noradrenergic pathways to elicit hyperactive voiding. Increase in NGF in the adult bladder due to pathological conditions yields similar, yet distinct, consequences for voiding behaviour and innervation. Likewise, increased NGF in adult bladders following obstruction or inflammation triggers neuronal hypertrophy, enhanced reflex activity and urinary frequency. In contrast to the SHR, hyper-innervation is not observed. Moreover, peripheral or spinal alpha-adrenoceptor blockade eliminates urinary frequency following obstruction. These observations support the role for sympathetic pathways in the motor function of the bladder, especially in congenital or adult disease states. A similar process may underlie the neuroplasticity involved in alterations after obstruction or inflammation of the lower urinary tract in humans. The SHR strain raises the possibility that a common genetic defect exists capable of predisposing to both hypertension and overactivity of the urinary bladder. Whether a genetic predisposition to sustained bladder overactivity in response to inflammatory stimuli in obstruction exists in humans is an intriguing prospect.

Exposure of rats to the pesticide and complex I inhibitor rotenone reproduces features of Parkinson's disease, including selective nigrostriatal dopaminergic degeneration and α-synuclein-positive cytoplasmic inclusions (Betarbet et al., 2000; Sherer et al., 2003). Here, we examined mechanisms of rotenone toxicity using three model systems. In SK-N-MC human neuroblastoma cells, rotenone (10 nmto 1 μm) caused dose-dependent ATP depletion, oxidative damage, and death. To determine the molecular site of action of rotenone, cells were transfected with the rotenone-insensitive single-subunit NADH dehydrogenase ofSaccharomyces cerevisiae(NDI1), which incorporates into the mammalian ETC and acts as a “replacement” for endogenous complex I. In response to rotenone, NDI1-transfected cells did not show mitochondrial impairment, oxidative damage, or death, demonstrating that these effects of rotenone were caused by specific interactions at complex I. Although rotenone caused modest ATP depletion, equivalent ATP loss induced by 2-deoxyglucose was without toxicity, arguing that bioenergetic defects were not responsible for cell death. In contrast, reducing oxidative damage with antioxidants, or by NDI1 transfection, blocked cell death. To determine the relevance of rotenone-induced oxidative damage to dopaminergic neuronal death, we used a chronic midbrain slice culture model. In this system, rotenone caused oxidative damage and dopaminergic neuronal loss, effects blocked by α-tocopherol. Finally, brains from rotenone-treated animals demonstrated oxidative damage, most notably in midbrain and olfactory bulb, dopaminergic regions affected by Parkinson's disease. These results, using three models of increasing complexity, demonstrate the involvement of oxidative damage in rotenone toxicity and support the evaluation of antioxidant therapies for Parkinson's disease.

Parkinson’s disease (PD), a common neurodegenerative disorder affects approximately 1% of the population over 65. PD is a late-onset progressive motor disease characterized by tremor, rigidity (stiffness), and bradykinesia (slowness of movement). The hallmark of PD is the selective death of dopamine-containing neurons in the substantia nigra pars compacta which send their projections to the striatum and the presence of cytoplasmic aggregates called Lewy bodies [1-2]. Most cases of PD are sporadic but rare cases are familial, with earlier onset. The underlying mechanisms and causes of PD still remain unclear.

Chronic systemic complex I inhibition caused by rotenone exposure induces features of Parkinson's disease (PD) in rats, including selective nigrostriatal dopaminergic degeneration and formation of ubiquitin- and alpha-synuclein-positive inclusions (Betarbet et al., 2000). To determine underlying mechanisms of rotenone-induced cell death, we developed a chronic in vitro model based on treating human neuroblastoma cells with 5 nm rotenone for 1-4 weeks. For up to 4 weeks, cells grown in the presence of rotenone had normal morphology and growth kinetics, but at this time point, approximately 5% of cells began to undergo apoptosis. Short-term rotenone treatment (1 week) elevated soluble alpha-synuclein protein levels without changing message levels, suggesting that alpha-synuclein degradation was retarded. Chronic rotenone exposure (4 weeks) increased levels of SDS-insoluble alpha-synuclein and ubiquitin. After a latency of >2 weeks, rotenone-treated cells showed evidence of oxidative stress, including loss of glutathione and increased oxidative DNA and protein damage. Chronic rotenone treatment (4 weeks) caused a slight elevation in basal apoptosis and markedly sensitized cells to further oxidative challenge. In response to H2O2, there was cytochrome c release from mitochondria, caspase-3 activation, and apoptosis, all of which occurred earlier and to a much greater extent in rotenone-treated cells; caspase inhibition provided substantial protection. These studies indicate that chronic low-grade complex I inhibition caused by rotenone exposure induces accumulation and aggregation of alpha-synuclein and ubiquitin, progressive oxidative damage, and caspase-dependent death, mechanisms that may be central to PD pathogenesis.

Complex I of the mammalian electron transfer chain is composed of at least 43 protein subunits, of which 7 are encoded by mtDNA. It catalyzes the transfer of electrons from NADH to ubiquinone and translocates protons from the mitochondrial matrix to the intermembrane space. It may also play direct roles in the mitochondrial permeability transition and in cell death pathways. Despite the limitations of current complex I assays, biochemical studies have suggested the presence of a mild, systemic defect of complex I in Parkinson's disease (PD). Recent experimental work has modeled this abnormality using rotenone to systemically inhibit complex I. Chronic rotenone exposure accurately recapitulated the pathological, biochemical, and behavioral features of PD. Thus, relatively subtle complex I abnormalities--either genetic or acquired--may be central to the pathogenesis of PD.

The cause of Parkinson's disease (PD) is unknown, but epidemiological studies suggest an association with pesticides and other environmental toxins, and biochemical studies implicate a systemic defect in mitochondrial complex I. We report that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity. Nigral neurons in rotenone-treated rats accumulate fibrillar cytoplasmic inclusions that contain ubiquitin and alpha-synuclein. These results indicate that chronic exposure to a common pesticide can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD.

Exposure of rats to the pesticide and complex I inhibitor rotenone reproduces features of Parkinson’s disease, including selective nigrostriatal dopaminergic degeneration and α-synuclein-positive cytoplasmic inclusions (Betarbet et al., 2000; Sherer et al., 2003). Here, we examined mechanisms of rotenone toxicity using three model systems. In SK-N-MC human neuroblastoma cells, rotenone (10 nM to 1μM) caused dose-dependent ATP depletion, oxidative damage, and death. To determine the molecular site of action of rotenone, cells were transfected with the rotenone-insensitive single-subunit NADH dehydrogenase of Saccharomyces cerevisiae (NDI1), which incorporates into the mammalian ETC and acts as a “replacement” for endogenous complex I. In response to rotenone, NDI1-transfected cells did not show mitochondrial impairment, oxidative damage, or death, demonstrating that these effects of rotenone were caused by specific interactions at complex I. Although rotenone caused modest ATP depletion, equivalent ATP loss induced by 2-deoxyglucose was without toxicity, arguing that bioenergetic defects were not responsible for cell death. In contrast, reducing oxidative damage with antioxidants, orbyNDI1 transfection, blocked cell death. To determine the relevance of rotenone-induced oxidative damage to dopaminergic neuronal death, we used a chronic midbrain slice culture model. In this system, rotenone caused oxidative damage and dopaminergic neuronal loss, effects blocked by α-tocopherol. Finally, brains from rotenone-treated animals demonstrated oxidative damage, most notably in midbrain and olfactory bulb, dopaminergic regions affected by Parkinson’s disease. These results, using three models of increasing complexity, demonstrate the involvement of oxidative damage in rotenone toxicity and support the evaluation of antioxidant therapies for Parkinson’s disease.

To investigate the role of chronic mitochondrial dysfunction on intracellular calcium signaling, we studied basal and stimulated cytosolic calcium levels in SH-SY5Y cells and a derived cell line devoid of mitochondrial DNA (Rho degrees ). Basal cytosolic calcium levels were slightly but significantly reduced in Rho degrees cells. The impact of chronic depletion of mitochondrial DNA was more evident following exposure of cells to carbachol, a calcium mobilizing agent. Calcium transients generated in Rho degrees cells following application of carbachol were more rapid than those in SH-SY5Y cells. A plateau phase of calcium recovery during calcium transients was present in SH-SY5Y cells but absent in Rho degrees cells. The rapid calcium transients in Rho degrees cells were due, in part, to increased reliance on Na(+)/Ca(2+) exchange activity at the plasma membrane and the plateau phase in calcium recovery in SH-SY5Y cells was dependent on the presence of extracellular calcium. We also examined whether mitochondrial DNA depletion influenced calcium responses to release of intracellular calcium stores. Rho degrees cells showed reduced responses to the uncoupler, FCCP, and the sarcoplasmic reticulum calcium ATPase inhibitor, thapsigargin. Acute exposure of SH-SY5Y cells to mitochondrial inhibitors did not mimic the results seen in Rho degrees cells. These results suggest that cytosolic calcium homeostasis in this neuron-like cell line is significantly altered as a consequence of chronic depletion of mitochondrial DNA.