International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 170 - MOUSE WT SNCA PROTECTS AGAINST HUMAN A53T SNCA-INDUCED SYNUCLEINOPATHY; HUMAN WT SNCA DOES NOT PROTECT

Cabin DE, Nussbaum RL

NHGRI/NIH, Bethesda, United States

a -synuclein (SNCA) has been linked to Parkinson's disease (PD) by rare disease-causing mutations and a chromosomal triplication.  It is also a major constituent of Lewy bodies, neuronal inclusions found in sporadic PD.  Non-physiological overexpression of human A53T mutant SNCA in mouse spinal cord causes a synucleinopathy leading to limb paralysis and death.  We showed that this phenotype is exacerbated in mice that lack endogenous Snca, although the normal level of the mouse protein in spinal cord is low.  We wished to determine if human WT SNCA confers similar protection by crossing a human WT SNCA PAC transgene onto the line lacking endogenous Snca but carrying the mutant human transgene.  The hWT transgene driven by its own promoter shows an expression pattern in mouse brain and spinal cord quite similar to that of mouse Snca.  Doubly transgenic mice that lack mouse Snca are currently developing the spinal cord neuronopathy at the same rate seen in the singly transgenic line, indicating that human WT SNCA does not provide the protection afforded by the mouse protein.  Identical pathology develops, with Wallerian degeneration in ventral roots.  Intracellular SNCA inclusions similar to pale bodies are found in motor neuron cell bodies in both lines.  Thus at least some of the 6 amino acid differences between the mouse and human proteins (besides that at position 53) must confer a significant difference in their properties.  Microarray analysis is currently being performed to better understand how the mutant human SNCA causes the spinal cord synucleinopathy.

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