Just how good are animal models of neurodegenerative disorders? After all, those based on genetic lesions recapitulate only aspects of human disease; this is true of both Alzheimer’s (see related information on animal models) and Parkinson’s (see, for example, companion news story on DJ-1 knockout mice). Are models based on toxic chemicals any better? Two papers in this week’s PNAS argue that it may. Francisco Perez and Richard Palmiter call into question the ability of parkin knockouts to mimic PD, while Thomas Sudhof and colleagues report that perhaps the best model of the disease can be elicited by the slow, continual administration of MPTP through osmotic minipumps.
Parkin knockouts have been developed before. Perez and Palmiter, at the University of Washington, Seattle, describe efforts to develop their own by deleting exon 2, the site of several mutations that give rise to autosomal recessive juvenile Parkinsonism (AR-JP). Although the knockout results in the loss of parkin protein, Perez and Palmiter found that their mutant mice lived just as long as their wild-type littermates. Examining three- to 22-month-old mice, the authors found no significant differences in body temperature, pain reception, and almost no differences in body weight between control and knockout animals.
Likewise, the authors found no differences in locomotor activity, strength, or various types of water maze testing, indicating that learning and memory are intact in the mutants. All told, the authors state that “we were unable to detect any behavioral abnormalities in parkin-deficient mice greater than what could be expected by chance.”
Yet others have found that different parkin knockouts exhibit deficiencies in at least some of these parameters (for example, see Goldberg et al., 2003; Itier et al., 2003; van Coelln et al., 2004 and ARF related news story). Perez and Palmiter write this about why their data is at odds with those reports: “The inconsistent phenotypes observed by different laboratories could be a consequence of genetic background differences between the mouse strains tested.”
The reasoning seems to lead back to the original question of the suitability of mice as models of human disease. The human population is not of the same genetic background, yet single point mutations in parkin are sufficient and certain to cause Parkinson disease in us. So are genetic models truly useful? The authors suggest that finding out why parkin-deficient mice do not exhibit Parkinsonism could advance our knowledge and treatment of the disease.
If the genetic models don’t prove useful, can chemical models save the day? The model described by Sudhof and coworkers from UT Southwestern University in Dallas, and their international collaborators in Italy and Germany, mimics the pathology seen in Parkinson disease fairly closely.
First author Francesco Fornai and colleagues used tiny osmotic pumps to slowly deliver the chemical MPTP to the animals. MPTP (or 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine) achieved notoriety in the 1980s when, as a contaminant in street heroin, it was found to induce Parkinsonism in drug addicts. Used in mice, it causes mitochondrial damage, particularly in the dopaminergic neurons most affected in PD, i.e., those in the substantia nigra of the midbrain. While MPTP causes nigral neuron loss, it hasn’t so far been shown to induce formation of the inclusions, or Lewy bodies, that are a hallmark of PD.
But Fornai and colleagues demonstrate that if the MPTP was delivered chronically, ubiquitin- and α-synuclein-containing inclusions do form. In addition, the proteasome activity in the nigral neurons was briefly inhibited by continual MPTP, as has been observed previously, and the number of dopaminergic neurons was dramatically reduced by as much as 80 percent at the highest doses (see also McNaught et al., 2004). But perhaps the most interesting observation was that the toxicity of MPTP is much reduced in α-synuclein knockout mice. In these animals, MPTP infusion caused no significant loss of dopaminergic neurons, the proteasome was less inhibited, and the inclusion bodies were reduced (by over twofold), though not completely eliminated.
The data suggest that this model recapitulates large portions of the pathology seen in humans, including the link between the ubiquitin proteasome system and α-synuclein. The authors also observed neurodegeneration of noradrenergic neurons in the locus coeruleus, also seen in Parkinson disease.—Tom Fagan
- PD Models: Loss of DJ Throws D2 Dopamine Receptor Out of Step
- Loss of Parkin in Mammals Takes Steam Out of Mitochondria
- Goldberg MS, Fleming SM, Palacino JJ, Cepeda C, Lam HA, Bhatnagar A, Meloni EG, Wu N, Ackerson LC, Klapstein GJ, Gajendiran M, Roth BL, Chesselet MF, Maidment NT, Levine MS, Shen J. Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem. 2003 Oct 31;278(44):43628-35. PubMed.
- Itier JM, Ibanez P, Mena MA, Abbas N, Cohen-Salmon C, Bohme GA, Laville M, Pratt J, Corti O, Pradier L, Ret G, Joubert C, Periquet M, Araujo F, Negroni J, Casarejos MJ, Canals S, Solano R, Serrano A, Gallego E, Sanchez M, Denefle P, Benavides J, Tremp G, Rooney TA, Brice A, Garcia de Yebenes J. Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet. 2003 Sep 15;12(18):2277-91. PubMed.
- von Coelln R, Thomas B, Savitt JM, Lim KL, Sasaki M, Hess EJ, Dawson VL, Dawson TM. Loss of locus coeruleus neurons and reduced startle in parkin null mice. Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10744-9. PubMed.
- McNaught KS, Perl DP, Brownell AL, Olanow CW. Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease. Ann Neurol. 2004 Jul;56(1):149-62. PubMed.
No Available Further Reading
- Perez FA, Palmiter RD. Parkin-deficient mice are not a robust model of parkinsonism. Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):2174-9. PubMed.
- Fornai F, Schlüter OM, Lenzi P, Gesi M, Ruffoli R, Ferrucci M, Lazzeri G, Busceti CL, Pontarelli F, Battaglia G, Pellegrini A, Nicoletti F, Ruggieri S, Paparelli A, Südhof TC. Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein. Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3413-8. PubMed.