Novel Familial Parkinson's Disease Model

JAX® NOTES Issue 491, Fall 2003

Dementia, a progressive global loss of cognitive function, affects up to half of the population 85  years and older. Alpha-synucleinopathies, which include syndromes such as familial Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, are the second leading cause of neurodegenerative dementia after Alzheimer's disease1. In addition to neuronal loss, characteristic brain lesions called Lewy bodies are exhibited in alpha-synucleinopathies. Lewy bodies are aggregations of insoluble filamentous alpha-synuclein protein that appear as intracytoplasmic inclusions in neurons and glial cells. The specific location and onset of Lewy body formation in the brain distinguish the various alpha-synucleinopathic syndromes. Distinction among the neurodegenerative syndromes is still in question, as there is an overlap of clinical and diagnostic features among Parkinson's disease, Alzheimer's disease, and other Lewy body syndromes.

Some familial Parkinson's disease is associated with mutations in the alpha-synuclein gene, which is a presynaptic protein of unknown function. One of these mutations, A53T, is an alanine to threonine substitution at amino acid residue 53 of alpha-synuclein. University of Pennsylvania School of Medicine researchers Drs. John Trojanowski and Virginia Lee have generated a line of transgenic mice called B6;C3H-Tg(SNCA)83Vle, that express mutant A53T human alpha-synuclein under the control of the mouse prion protein (Prnp) promoter2. The Prnp promoter has been shown to drive high levels of expression in most neurons of the central nervous system. By eight months of age, homozygous B6;C3H-Tg(SNCA)83Vle mice begin to develop a progressive phenotype characterized by weight loss, lack of grooming and reduced movement followed by partial and then complete limb paralysis accompanied by neurodegeneration. Concomitant with the progressive phenotype, these mice develop age-dependent intracytoplasmic neuronal inclusion bodies, similar to those seen in patients affected with alpha-synucleinopathies. The inclusions contain 10-16 nm fibrils that are recognized by antibodies specific for human alpha-synuclein (See Figure 1). Researchers theorize that if inclusion formation can be inhibited or reversed, this could lead to novel therapeutic approaches.

Figure 1. Immunoelectron microscopy of inclusion body filament from the cerebellum of an 11 month old homozygous B6;C3H-Tg(SNCA)83Vle (Stock Number 004479) mouse. The antibody used (Syn 303) recognizes human alpha-synuclein.

This figure was reprinted from "Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM. Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 2002; 34:521-533." with permission from the authors and Elsevier.

Drs. Trojanowski and Lee have kindly donated their B6;C3H-Tg(SNCA)83Vle (Stock Number 004479) mice to the Induced Mutant Resource at The Jackson Laboratory. A distribution colony is currently in development. If you are interested in purchasing these mice, please contact Customer Service and request that your name be added to the interest list. Alternatively, you may register your interest on-line. To do this, visit the JAX® Mice Database at: www.jax.org/jaxmice.

References
  1. Gavin JE. Dementia with Lewy Bodies. Alzheimer Disease Research Center (ADRC) at Washington University Medical Center, St. Louis. (www.alzheimer.wustl.edu/adrc2/Education/LewyBody/LBMain.htm) accessed July 31, 2003.
  2. Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, and Lee VM. Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 2002; 34:521-533.