International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany

Plenary Presentations * Oral Presentations *
Poster Presentations: Behavioural Genetics and Genomics * Development and Stem Cells * Functional Genome Analysis * Mouse Models of Human Disease * Mouse System Biology Bioinformatics * Multigenic and Multifactorial Trait Analysis * Nutrition and Metabolic Disease * Phenotyping Methods Imaging * The Genetics and Genomics of Infectious Disease *
Verne Chapman Memorial Lecture * Table of Contents * Sponsor/Exhibitor List * Awards * Photographs

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ORAL PRESENTATION

TUESDAY 11 NOVEMBER
09:30 – 09:45 HRS

DELETION OF THE ENDOGENOUS MOUSE SNCA GENE MARKEDLY EXACERBATES SYNUCLEINOPATHY IN TRANSGENIC MICE EXPRESSING ALA53>THR HUMAN α-SYNUCLEIN

Cabin D E
NHGRI/NIH

Co-Authors: 2) Gispert-Sanchez S, 3) Murphy D, 2) Auburger G, 4) Myers R,1) Nussbaum R
Institutions: 1) NHGRI/NIH 2) University Hospital, Frankfurt/M, Germany 3) NINDS/NIH 4) University of California at San Diego

Mutations in the α-synuclein gene ( SNCA) are known to cause Parkinson's disease (PD) in a subset of familial cases. The normal function of α-synuclein is unknown, but it is a component of Lewy bodies, neuronal inclusions diagnostic for PD. An A53T mutant human SNCA transgene driven by the mouse prion promoter was crossed into mice lacking endogenous α-synuclein. Knockout mice expressing only human A53T α-synuclein develop a spinal cord neuropathy characterized by limb weakness and paralysis with earliest onset at 16 months of age. The spinal cord pathology is probably due to nonphysiological expression of the transgene in the ventral spinal cord, leading to Wallerian degeneration in the ventral roots. Mice carrying this transgene on a WT background show mild neuronal dysfunction, but only rarely develop the severe neuropathy and then only at a later age. These results indicate that mouse α-synuclein is protective against the deleterious effects of the human mutant protein, even though the most severe pathology is in a region that normally has low expression of endogenous mouse α-synuclein. At position 53, the wild type amino acid in the mouse is a threonine, the amino acid that causes PD in humans, indicating that mice are either too short-lived to suffer ill effects from that residue, or else have evolved means to protect against it. We conclude that the best approach to developing a realistic mouse model for PD will be to express human SNCA transgenes in mice that lack endogenous α-synuclein, in only the appropriate tissues.