Assistant Professor, Departments of Neurology and Molecular and Human Genetics
Adjunct Assistant Professor, Department of Biochemistry and Cell Biology, Rice University

M.D., University of Padua School of Medicine, Italy, 1990
Research Fellow, University of Padua School of Medicine, Italy, 1992
Postdoctoral Fellow,Columbia University, 1997
Resident in Neurology, University of Michigan, 2001
Fellow in Clinical Genetics and Postdoc, Baylor College of Medicine, 2004

RESEARCH INTERESTS:

The overall goal of my research program is to elucidate genetic and biochemical pathways of neuronal function and gene-environment interactions in the brain and to apply this knowledge to neurological disorders caused by dysfunction in these pathways. As model systems, we study Parkinson’s disease, a common neurodegenerative disorder that causes progressive motor disability in adults, and Rett syndrome, an autism spectrum disorder that generally affects 1-2 year-old girls.

Parkinson’s disease is a multifactorial neurological disorder. Several genes have been implicated in its pathogenesis and environmental factors have been shown to either cause parkinsonism (post-encephalitic parkinsonism and MPTP) or to be associated with an increased risk of Parkinson’s disease (rural living, pesticide use, well-water consumption and certain occupations). Lipid and vesicle dynamics, the ubiquitin–proteasome system, MAPKKK signaling, oxidative stress, mitochondrial function and microtubule stability have all been implicated in the pathogenesis of Parkinson’s disease. However, the relationships between these pathways remain to be elucidated. Furthermore, the molecular interactions between genetic and environmental factors are largely unknown, a key issue considering that the majority of Parkinson’s disease cases occur sporadically. We have taken a system-wide genetic approach to identify the interrelationship between pathways of molecular dysfunction in Parkinson’s disease. Our aim is the elucidation of the molecular pathogenesis of Parkinson’s disease and the design of preventative or neuroprotective treatment strategies.

Rett syndrome is an X-linked dominant neurodevelopmental disorder caused by mutations in the gene encoding Methyl-CpG binding protein 2 (MeCP2). Affected children have cognitive impairment, autistic manifestations and motor dysfunction. We have identified abnormalities in all three of these domains in Mecp2 308 mutant mice, demonstrating that these animals represent a faithful model of the human disorder. We are now pursuing the elucidation of genetic and cellular pathways affected by MeCP2 dysfunction and the identification of epigenetic strategies for modification of disease severity in Rett syndrome. MeCP2 is a DNA methylation-dependent transcriptional repressor and methyl donors such as folate and betaine modulate metastable DNA methylation. We have shown that dietary methyl donors modify disease severity in Mecp2 mutant mice improving general health, neurological function and survival. Studies are ongoing to reveal the mechanisms of pathogenesis and epigenetic modification of disease severity using a combination of genetic and molecular approaches.

SELECTED PUBLICATIONS:

1. Moretti P, Peters SU, Del Gaudio D, Sahoo T, Hyland K, Bottiglieri T, Hopkin RJ, Peach E, Min SH, Goldman D, Roa B, Bacino CA, Scaglia F (2008). Brief Report: Autistic Symptoms, Developmental Regression, Mental Retardation, Epilepsy, and Dyskinesias in CNS Folate Deficiency. J. Autism Dev. Disord. 38: 1170-1177.

2. Moretti P, Zoghbi H (2006). MeCP2 Dysfunction in Rett Syndrome and Related Disorders. Curr. Opin. Genet. Dev. 16: 276-281.

3. Moretti P, Levenson J, Battaglia F, Atkinson R, Teague R, Antalffy B, Armstrong D, Arancio O, Sweatt D, Zoghbi H (2006). Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. J. Neurosci. 26: 319-327.

4. Moretti P*, Bouwknecht JA*, Teague R, Paylor R, Zoghbi H (2005). Abnormalities of Social Interactions and Home Cage Behavior in a Mouse Model of Rett Syndrome. Hum. Mol. Genet. 14: 205–220. (*equal contribution)

5. Moretti P, Sahoo T, Hyland K, Bottiglieri T, Peters S, delGaudio D, Roa B, Curry S, Zhu H, Finnell R, Neul J, Ramaekers V, Blau N, Bacino C, Miller G, Scaglia F (2005). Cerebral Folate Deficiency with Developmental Delay, Autism and Response to Folinic Acid. Neurology 64: 1088.

6. Moretti P, Hedera P, Wald J, Fink J (2005). Autosomal Recessive Primary Generalized Dystonia in Two Siblings from a Consanguineous Family. Mov. Disord. 20: 245-247.

7. Moretti P, Lieberman A, Wilde E, Giordani B, Kluin K, Koeppe R, Minoshima S, Kuhl D, Seltzer W, Foster N (2004). Novel Insertional Presenilin 1 Mutation Causing Alzheimer Disease with Spastic Paraparesis. Neurology 62: 1865-1868.

8. Moretti P, Shore D (2001). Multiple Interactions in Sir Protein Recruitment by Rap1p at Silencers and Telomeres in Yeast. Mol. Cell. Biol. 23: 8082-8094.

9. Marcand S, Buck SW, Moretti P, Gilson E, Shore D (1996). Silencing of Genes at Non-Telomeric Sites in Yeast is Controlled by Sequestration of Silencing Factors at Telomeres by Rap1 Protein. Genes Dev. 10: 1297-1309.

10. Moretti P, Freeman K, Coodly L, Shore D (1994). Evidence that a Complex of SIR Proteins Interacts with the Silencer and Telomere Binding Protein RAP1. Genes Dev. 8: 2257-2269.

For more publications, see listing on Pub Med.

CONTACT INFORMATION:

Paolo M. Moretti, M.D.
Departments of Neurology and Molecular and Human Genetics
Baylor College of Medicine
One Baylor Plaza, NB413
Houston, TX 77030, U.S.A.

Phone: 713-798-7573 (office) 713-798-7574 (lab)
Fax: 713-798-2723
E-mail:

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