Overview
Alzheimer's disease (AD) and Parkinson's disease (PD) are neurodegenerative diseases with no cures or even effective long-term therapies. Research into these diseases has uncovered various genetic and environmental factors that, in addition to the aging process, may increase the risk and/or age of onset for disease progression. However, the underlying mechanisms of disease initiation and progression remain unknown. My work focuses on creating and characterizing mouse models that accurately model human disease and therefore can be used to understand neurodegenerative disease and be used in the development of new therapies. I also serve as a resource for scientists seeking information about existing mouse models, and oversee the selection, importation and distribution of new AD and PD models.
Scientific report
Mouse models of neurodegenerative diseases
Alzheimer's disease (AD) and Parkinson's disease (PD) are neurodegenerative diseases with no cures or even effective long-term therapies. Research into these diseases has uncovered various genetic and environmental factors that, in addition to the aging process, may increase the risk and/or age of onset for disease progression. However, the underlying mechanisms of disease initiation and progression remain unknown. My work focuses on creating and characterizing mouse models that accurately model human disease and therefore can be used to understand neurodegenerative disease and be used in the development of new therapies. I also serve as a resource for scientists seeking information about existing mouse models, and oversee the selection, importation and distribution of new AD and PD models.
Alzheimer's Disease Mouse Model Repository
Alzheimer's disease is the most common cause of dementia. It is characterized by brain pathology including amyloid plaques composed of Abeta and intracellular tangles made up of hyperphosphorylated tau protein. Abeta is a cleavage product of the amyloid precurser protein (APP), and mutations in APP and its processing enzymes (including the presenilins, Bace) are thought to be one cause of AD.
The Jackson Laboratory offers a variety of genetic models for AD research, including strains expressing APP and presenilin (PSEN1) mutations, strains expressing mutant APP in either a constitutive or inducible manner, strains expressing mutant tau (Mapt), strains with Presenilin mutations, strains with Apoe mutations, and strains with Bace mutations. These models develop Alzheimer's-related characteristics as they age. In addition, numerous novel strains carrying alleles of other genes that have been identified as potential targets for AD therapies or AD risk genes by GWAS have been identified and imported for distribution. Many of these are thought to play a role in regulating the production or degradation of Abeta.
AD models are made congenic on inbred strains by the repository to stabilize the genetic background and ensure that phenotypic characteristics do not vary within a cohort or over time.
Parkinson's Disease Mouse Model Resource (PDMMR)
Parkinson's disease is characterized by the loss of dopamine-producing cells in the substantia nigra. While the earliest and most obvious symptoms are movement disorders including tremor, rigidity, gait abnormalities and bradykinesia (slowness of movement), there are many other manifestations, including cognitive, emotional, and sleep disorders. Accumulation of alpha-synuclein deposits in the brain lead to the formation of Lewy bodies, a diagnostic marker of PD.
The PDMMR is funded by the Michael J. Fox Foundation (MJFF) to provide genetically engineered mice and information useful for their selection and use. The Repository distributes Parkinson's disease models that are useful for the study of the basic pathophysiology of PD and for testing new therapies. The resource maintains and distributes more than 25 mouse models, which display certain disease characteristics, as well as dozens of related strains, with numerous more strains in development.
PD models include transgenic lines expressing human LRRK2, alpha-synuclein (SNCA), or parkin (Park2) with various disease-causing mutations. In some models, the transgenes have been designed so their expression can be regulated using the tet- or cre-systems. Complementary strains that express cre or tet in relevant brain regions or neuronal subtypes are also available. For basic studies, genetic knockouts of many PD-related genes are available, including alpha-, beta-, and gamma-synuclein (Snca, Sncb, Sncg), Lrrk1 and Lrrk2, Park2, DJ-1 (Park7) and Pink1.
Projects are ongoing to design, develop and characterize new knockout, point mutation and transgenic strains developed specifically for MJFF. Unlike most PD models developed to date, these will be available to pharmaceutical and biotechnology companies for use in the development and testing of potential therapies. The MJFF-funded pdonlineresearch.org website has a research models page listing and linking to JAX PD models.
Lab staff
Principal Investigator: Mike Sasner, Ph.D.
Technical Information Scientists: Melissa Berry, Alicia Valenzuela
Executive Assistant: Aimée Picard
Publication listings
Selected publications
Ringwald M, Mangan M, Eppig JT, Kadin JA, Richardson JE and the Gene Expression Database Group. 2000. GXD: a Gene Expression Database for the laboratory mouse. Nucleic Acids Res 28(1):115-119. PMCID: PMC102464
Ringwald M, Mangan M, Eppig JT, Kadin JA, Richardson JE and the Gene Expression Database Group. 1999. GXD: a Gene Expression Database for the laboratory mouse. Nucleic Acids Res 27(1):106-112. PMCID: PMC148107
Portilla D, Crew M, Grant D, Gerrero G, Bates L, Dai G, Cheng J, Sasner M, Buonanno A. 1998. cDNA cloning and expression of a novel family of enzymes with calcium-independent phospholipase A2 and lysophospholipase activities. J Am Soci Nephrol 9:1178-1186.
Ozaki M, Sasner M, Yao R, Lu H, Buonanno A. 1997. Neuregulin-b induces expression of an NMDA receptor subunit. Nature 390:691-694.
Sasner M, Buonanno A. 1996. NMDA receptor 2B gene sequences differentially regulating tissue- and developmental-specific transcription in transgenic mice. J.B.C. 271(35):21316-21322.
Sasner JM, Van Houten JL. 1989. Evidence for a Paramecium folate chemoreceptor. Chem Senses 14:587-595.