The Morris K. Udall Center for Excellence in Parkinson’s Research at MGH/MIT

 

 

Director: Anne B. Young, M.D., Ph.D.

Central Theme

The Udall Center at the Massachusetts General Hospital/Massachusetts Institute of Technology focuses on understanding the mechanisms that influence the pathology of Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB), and the complications of antiparkinsonian therapy.

 

Center Structure

Anne B. Young, MD, PhD is the Director of the MGH/MIT Udall Center. The Center has four scientific projects and three cores. Two projects are at MIT (Drs. Susan Lindquist and Ann Graybiel) and two are at MGH (Drs. Bradley Hyman and Anne Young). The Administrative Core supports all the projects and cores. The Neuropathology/Clinical Core supports the longitudinal cohort, Projects 1 and 4. The Bioinformatics Core supports projects 2, 3 and 4.

 

Recent Significant Advances

The Center has provided important contributions to our understanding of Parkinson’s disease. Dr. Hyman’s group has developed several assays to study alpha-synuclein (α-syn) aggregation and toxicity in vitro and in vivo and is exploring the role of molecular chaperones in Lewy body diseases with a view to the development of novel therapeutics for PD. Dr. Lindquist has identified modifiers of alpha-synuclein toxicity in yeast and is exploring the mechanism of the toxic process. Dr. Graybiel has shown that parkinsonian rodents do not learn normally and their striatal activity does not exhibit plastic changes during the acquisition of a behavior. In collaboration with Project 4, she identified a correlation of CalDAG-GEF1 and 2 proteins with the development of levodopa-induced dyskinesias (LID). Thyrotropin releasing hormone (TRH) is similarly regulated. Project 4 has also discovered gender-specific alterations in gene and protein expression in the substantia nigra (SN) and the temporal cortex of control, PD and DLB brains.

 

Available Resources

Resources available from MGH

Core B organizes the Udall Brain Bank that is run in close conjunction with the Alzheimer’s Disease Research Center Brain Bank (ADRC) at MGH.

In vitro αSyn aggregation and toxicity assays based on overexpression of:

• Wild-type αSyn
• Syn-T and synphilin-1
• GFP, Venus, and luciferase complementation pairs

In vivo models:

• Masliah Line D mice
• Masliah synuclein-EGFP mice
• Targeted overexpression of αSyn in rodent SN

Resources available from the Whitehead (MIT)

• Yeast strains expressing non-toxic, protein-tagged constructs, including an αSyn-DsRed yeast strain used for co-localization studies with GFP-tagged vesicle trafficking proteins.
• Drosophila, C. elegans, and rat Rab1 orthologs of hits from the yeast screen genes (e.g. suppressors YPT1, YOR291w, YCK3, CDC5, HRD1, UBP3, camp PDE, Hrd1/SYVN1, Ubp3/USP10, Pde2/PDE9A, Cdc5/PLK2, Yck3/CSNK1G3; enhancers: SIT4/PPP6C, PMR1/ATP2C1) have been cloned and introduced into viral expression vectors for use in these animal models.
• A suite of Gateway™ vectors for high-throughput genetic analysis in Saccharomyces cerevisiae, has been made available through Addgene: http://www.addgene.org/yeast_gateway
• ResponseNet: a computational algorithm that connects genetic and transcriptional data by known molecular interactions.

 

Plans for the Coming Year

Project 1 (Bradley Hyman, MD, PhD)

Our project uses in vitro cell culture models and in vivo models to examine the effect of molecular chaperones on α-syn aggregation and toxicity. In addition to the in vitro models described in the parent grant, we have developed a further in vitro model during the current funding period, based on a novel protein complementation assay, with which to study α-syn aggregation and toxicity and the impact of molecular chaperones and co-chaperones. The in vitro protein complementation assay to measure α-syn aggregation and toxicity is a natural progression of our original in vitro model. We will continue the studies envisioned in the parent grant, and reported in progress reports, to encompass our newly developed in vitro model based on protein complementation to study α-syn aggregation and toxicity. In accordance with our aims and hypotheses, we will continue our studies on αSyn aggregation and toxicity in the context of extracellular αSyn and examine the role of heat shock proteins (HSPs) on extracellular misfolded α-syn aggregation and toxicity.

Project 2 (Susan Lindquist, PhD)

The yeast model has allowed us to establish that α-syn is part of highly conserved genetic interactome. We also identified a suppressor from this screen as the homolog of the human PARK9 gene, confirming our yeast model’s predictive value for the human disease. Our overarching goal is to understand how these genetic modifiers with diverse functions relate to each other, and how they connect to the toxic oligomeric species of α-syn that have been described by so many other investigators. The parent grant comprises three hypotheses, all of which will be examined over the next year.

Project 3 (Ann Graybiel, PhD)

In our parent grant, we identified genes that might contribute to the occurrence of levodopa-induced dyskinesias in a 6-hydroxydopamine (6-OHDA) model of unilateral parkinsonism. Two genes that we had originally discovered, genes respectively enriched in the striosome and matrix compartments of the striatum, were dysregulated in proportion to the amount of dyskinesias expressed in the model, and their dysregulation was in opposite directions so that the striosome-enriched gene was upregulated as the matrix-enriched gene was downregulated. These findings support the hypothesis that the balance between striosome and matrix functions might be altered in dyskinesias just as this balance is thought to be altered in the case of drug-induced stereotypies. We propose experiments to directly test this hypothesis by examining the effect of selective ablation of striosomes in medial or lateral striatum before or after the development of dyskinesias in the 6-OHDA model. We hypothesize that this disruption of striosome function will lessen the expression of levodopa-induced dyskinesias (LID). We will follow up on the molecular basis for behavioral differences or similarities between the standard model and the striosome-depleted model of LID by comparative microarray analyses for gene expression changes. The combination of behavioral and bioinformatics data provided by these experiments should produce powerful evidence regarding the neural mechanisms underlying the development of LID in Parkinson’s disease and related movement disorders

Project 4 (Anne B. Young, MD, PhD)

Project 4 has investigated the issue of gene dysregulation in the diseased tissue, and was able to show that this dysregulation was strongly influenced by the gender of the patient. We are now investigating the influence of gender on specific gene pathways and on the metabolism, catabolism and accumulation of alpha-synuclein in the human diseased brain and in animal models of alpha-synuclein pathology.

A collaborative effort with Project 3 has identified a host of novel genes regulated by the development of levodopa-induced dyskinesias (LID). We will continue to examine the role of one of these genes, i.e. thyrotropin releasing hormone (TRH). TRH is the gene that showed the highest upregulation in response to the development of LID and the best correlation with the behavioral measures of LID. We will investigate the timeline of the up-regulation of striatal TRH in response to dopamine depletion and replacement. This will allow us to better understand the relationship between the hormone d LID.

 

Select Recent Publications

Yeger-Lotem E, Riva L, Su LJ, Gitler AD, Cashikar AG, King OD, Auluck PK, Geddie ML, Valastyan JS, Karger DR, Lindquist S, Fraenkel E. Bridging the gap between high-throughput genetic and transcriptional data reveals cellular pathways responding to alpha-synuclein toxicity. Nat Genet, 2009, 41(3): 316-23. NIHMSID: NIHMS109987

Crittenden, J. R., Cantuti-Castelvetri, I., Saka, E., Keller-McGandy, C. E., Hernandez, L. F., Kett, L. R., Young, A. B., Standaert, D. and Graybiel, A. M. (2009) Dysregulation of CalDAG-GEFI and CalDAG-GEFII predicts the severity of motor side-effects induced by anti-parkinsonian therapy. PNAS. 2009, 106:2892-2896.

Gomperts SN, Rentz DM, Moran E, Becker JA, Locascio JJ, Klunk WE, Mathis CA, Elmaleh DR, Shoup T, Fischman AJ, Hyman BT, Growdon JH, Johnson KA. Imaging amyloid deposition in Lewy body diseases. Neurology. 2008, 71(12): 903-10.

Yacoubian TA, Cantuti-Castelvetri I, Bouzou B, Asteris G, McLean PJ, Hyman BT, and Standaert DG. Transcriptional Dysregulation in a Transgenic Model of Parkinson’s Disease. Neurobiol. Dis., 2008, 29(3): 515-528 [Epub 2007 Nov 28]

Outeiro TF, Putcha P, Tetzlaff JE, Spoelgen S, Koker M, Carvalho F, Hyman BT, and McLean PJ. Formation of toxic oligomeric alpha-synuclein species in living cells. PLoS ONE, 2008, 3(4) e1867. PMCID: PMC2270899

Tetzlaff JE, Putcha P, Outeiro TF, Ivanov A, Berezovska O, Hyman BT, and McLean PJ. Chip targets toxic alpha-synuclein oligomers for degradation. J. Biol. Chem., 2008, 283(26):17962-8. [Epub 2008 April 25].

Theodore S, Cao S, McLean PJ, and Standaert DG. Targeted overexpression of human a-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson’s disease. J. Neuropathol. Exp. Neurol., 2008, 67(12):1149-1158

McFarland NR, Lee JS, Hyman BT, and McLean PJ. Comparison of Transduction Efficiency of Recombinant AAV Serotypes 1, 2, 5, and 8 in the Rat Nigrostriatal System. J. Neurochem., 2009, 109(3):838-845 [Epub 2009 Feb 24]. PMCID: PMC2698947

McFarland NR, Fan Z, Xu K, Schwarzschild MA, Feany MB, Hyman BT, and McLean PJ. Alpha-synuclein S129 phosphorylation mutants do not alter nigrostriatal toxicity in a rat model of Parkinson disease. J. Neuropathol. Exp. Neurol., 2009, 68(5):515-524

Outeiro TF, Klucken J, Bercury K, Tetzlaff JE, Putcha P, Oliveira LMA, Quintas A, McLean PJ, and Hyman BT. Dopamine-induced conformational changes in alpha-synuclein. PLoS ONE, 2009, In press

 

Public Health Statement

Our Center focuses on understanding the mechanisms that influence the pathology of Parkinsons Disease (PD) and Dementia with Lewy Bodies (DLB), and the complications of antiparkinsonian therapy. The Center has four scientific projects and three cores. The Administrative Core supports all the projects and cores. The Neuropathology/clinical Core supports the group of patients followed longitudinally, Projects 1 and 4. The Bioinformatics Core supports projects 2, 3 and 4. The Center has provided important contributions to our understanding of Parkinson’s disease. Dr. Hyman’s group has developed several assays to study alpha-synuclein aggregation and toxicity in vitro and in vivo and is exploring the role of molecular chaperones in Lewy body diseases with a view to the development of novel therapeutics for PD. Dr. Lindquist has identified modifiers of alpha-synuclein toxicity in yeast and is exploring the mechanism of the toxic process. Dr. Graybiel has shown that parkinsonian rodents do not learn normally and their striatal activity doesn’t go through plastic changes during the acquisition of a behavior. In collaboration with Project 4, she identified a correlation of CalDAG-GEF1 and 2 proteins with the development of levodopa-induced dyskinesias. Thyrotropin releasing hormone is similarly regulated. Project 4 has also discovered gender-specific alterations in gene and protein expression in the substantia nigra and the temporal cortex of control, PD and DLB brains.