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Center on Aging

Dopamine PPG

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Dual-hit hypothesis of aging-related DA dysfunction
Program Project Grant AG023630, National Institutes on Aging, PI: Ann-Charlotte Granholm
Departments of Neuroscience, Ophthalmology, Psychiatry and Laboratory Animal Research, MUSC

Parkinson's disease (PD) is a neurological disorder that afflicts an increasing number of individuals. If the wider complex of extrapyramidal symptoms referred to as parkinsonian syndrome (PS) is included, the incidence is near 50% of the population over 80 years of age (Bennett et al., 1996; Mandel et al., 2003; see also Granholm et al., 2008). Currently there are no treatment paradigms that will stem the degenerative aspect of the disease, and the etiology is still unknown, although it is well recognized that age is the number one risk factor for PS (Eggers, 2009; Bennett et al., 1996). The primary goal of our research program is to identify the neurobiological underpinnings of age-related motor dysfunction related to PS. We utilize novel and progressive mouse models, and identify novel pharmacological treatments for neuroprotection of central dopaminergic (DA) neurons. Our focus is the neurotrophic factor glial cell line-derived neurotrophic factor (GDNF), which has been a major component in the Granholm laboratory for the last two decades and is one of two major research lines in our Program Project Grant in the current funding period.  GDNF is a powerful trophic factor for dopamine (DA) neurons in the brain, and has been proposed as a therapeutic treatment for PD patients (Gill et al., 2003).

Parkinson's Disease: Circuitry and Treatment Avenues: The basal ganglia consist of the striatum, the external and internal segments of the globus pallidus (GPe and GPi, respectively), the pars compacta and pars reticulata of the substantia nigra (SNc and SNr, respectively), and the subthalamic nucleus (STN). These structures are linked via a complex network of excitatory and inhibitory connections (shown as + and - in the schematic, Figure 1). Alterations occurring in idiopathic PD and in parkinsonism modeled here, include degeneration of the DA input to striatum from SN (red arrows in Fig. 1), elevated GABA output from the striatum, and elevated glutamate input to the SN pars reticulata (SNr) and Globus pallidus (yellow lines, Figure 1). Although there is effective symptomatic therapy for PD that can provide most patients with several years of satisfactory quality of life and response to treatment (Baron, 2005), there are no proven neuroprotective treatments for the disease. (Boger et al., 2009 for review).



Figure 1
. Parkinsonian brain circuits, including loss of DA input to the striatum(red), reduced GDNF transport to SN from striatum ( dark blue), increased GABAergic output from the striatum (light blue) and increased glutamate input to the SN (yellow)

It is likely that a combination of hereditary predisposition and environmental factors play a role in the motor impairment that develops with age. Therefore, this PPG is focused on the "dual-hit" hypothesis, by combining hereditary (Gdnf mutation) and environmental neurotoxins exposure to determine long-term effects on the DA system. Our studies in the current funding period have confirmed the dual-hit hypothesis by demonstrating significant additive effects of neurotoxins upon the DA neurons in growth factor deleted mice (see Boger et al., 2007). In the competing renewal of this PPG, we propose to utilize conditional Gdnf knockout mice, and also to develop treatment paradigms which can counteract inflammatory or oxidative stress aspects of parkinsonism. By studying two different external toxins (LPS in Project 1, MPTP/p in Project 2, and both in Project 5), in combination with a genotype that has reduced GDNF levels, we will be able to determine what is common and what is different between our different models. We believe that the pathogenic process may be the same in many cases, and we will have the unique ability to test this within our investigator group.

Ongoing studies in the PPG: During the current grant period, we examined the long-term effects of partial gene deletion of Gdnf and Bdnf combined with the aging process using Bdnf+/- and Gdnf+/- mice. Project 1 discovered compelling evidence for a dual-hit effect of prenatal LPS (a common product of gram-negative bacterial infection) administration + Gdnf gene knockout on the DA system. Project 2 found a significant interaction between methamphetamine (METH) treatment and Gdnf, but not Bdnf, partial gene deletion on striatal DA innervation, leading to exacerbated decline in motor function, especially in the middle-aged mouse. Based on our recent findings, our future emphasis will be on the effects of GDNF loss when the nigrostriatal DA system is challenged with a potent inflammogen (lipopolysaccharide-LPS) or mitochondrial complex I challenge (1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine, MPTP).

Our findings demonstrate that DA neurons in mice with a partial deletion of the Gdnf gene (Gdnf+/- mice) exhibit exacerbated vulnerability to neurotoxins, especially in middle-aged or aged subjects, supporting our overall hypothesis that a genetic predisposition combined with environmental factors can "set the stage" for progressive motor dysfunction and DA neuronal degeneration occurring with aging.


Investigators:

Project 1 and Overall PI: Ann-Charlotte Granholm, Neuroscience
Co-Director: Larry Middaugh, Psychiatry
Project 2: Jakie McGinty, Neuroscience
Project 5: Ingrid Strömberg, Umeå University, Sweden
Core A, Administrative Core: Granholm, Middaugh, and Patrick Randall (Psychiatry)
Core B Animal Core: Kris Helke, DLAR and Baerbel Rohrer, Ophthalmology
Core D, Drug Discovery Core: Baerbel Rohrer, Mona Buhusi (Neuroscience, collaborator)


Publications:

  • Boger et al. 2006 (Project 1): A Partial GDNF depletion leads to earlier age-related deterioration of motor fuction and tyrosine hydroxylase expression in the substantia nigra 
  • Boger et al. 2007 (Project 2): Long-Term Consequences of Methamphetamine Exposure in Young Adults are Exacerbated in Glial Cell Line-Derived Neurotrophic Factor Heterozygous Mice
  • Boger et al. 2008 (Project 1): Differential effects of the dopamine neurotoxin MPTP in animals with a partial deletion of the GDNF receptor, GFRα1, gene
  • Boger et al. 2009 (Project 2): Minocycline restores striatal tyrosine hydroxylase in GDNF heterozygous mice but not in methamphetamine-treated mice
  • af Bjerken et al. 2007 (Project 5): Effects of glial cell line-derived neurotrophic factor deletion on the ventral mesencephalic organotypic tissue cultures
  • af Bjerken et al. 2008 (Project 5): Inhibition of astrocytes promotes long-distance growing nerve fibers in ventral mesencephalic cultures
  • Quintero et al. 2004: Glial cell line-derived neurotrophic factor is essential for neuronal survival in the locus coeruleus-hippocampal noradrenergic pathway
  • Quintero et al. 2006: Behavioral and morphological effects of minocycline in the 6-hydroxydopamine rat model of Parkinson's disease
  • Griffin et al. 2006: Partial deletion of glial cell-lined-derived neurotrophic factor (GDNF) in mice: Effects on sucrose reward and striatal GDNF concentrations
  • Zaman et al. 2008: The nigrostriatal dopamine system of aging GFRα-1 heterozygous mice: neurochemistry, morphology and behavior
  • Granholm et al. 2008: Mood, Memory and Movement: An Age-Related Neurodegenerative Complex?
  • Appendices List 05-09

Literature cited:

Baron, M.S. 2005. Movement disorders in the older patient: differential diagnosis and general management. Cleveland Clinic Journal of Medicine 72 Suppl 3, S38-51.

Bennett, D.A., Beckett, L.A., Murray, A.M., Shannon, K.M., Goetz, C.G., Pilgrim, D.M., Evans, D.A.  1996.  Prevalence of parkinsonian signs and associated mortality in a community population of older people.  N Engl J Med 334, 71-76.

Boger, H.A., Middaugh, L.D., Patrick, K.S., Ramamoorthy, S., Denehy, E.D., Zhu, H., Pacchioni, A.M., Granholm, A.C., McGinty, J.F. 2007. Long-term consequences of methamphetamine exposure in young adults are exacerbated in glial cell line-derived neurotrophic factor heterozygous mice. J Neurosci 27, 8816-8825.

Boger, HA. Granholm, A-Ch., McGinty J., and Middaugh, L.D. (2009) A dual-hit hypothesis for age-related Parkinsonism. Prog. Neurobiology (in press).

Eggers A.E. (2009) Why do Alzheimer's disease and Parkinson's disease target the same neurons? Med Hypotheses. Jun;72(6):698-700. Epub

Gill, S.S., Patel, N.K., Hotton, G.R., O'Sullivan, K., McCarter, R., Bunnage, M., Brooks, D.J., Svendsen, C.N., Heywood, P.  2003.  Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease.  Nat Med 9, 589-595.

Granholm A-Ch., Boger H.A., and Emborg M.E. 2008. Mood, memory, and movement: An age-related neurodegenerative complex? Current Aging Science 1: 133-139.

Mandel, S., Grunblatt, E., Riederer, P., Gerlach, M., Levites, Y., Youdim, M.B. 2003. Neuroprotective strategies in Parkinson's disease : an update on progress. CNS Drugs 17, 729-762.

 
 
 

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