alpha-Synuclein-based Model for Studying Parkinsons Disease Pathology

Parkinson's disease (PD) is a multicentric, progressive neurodegenerative disorder that strikes approximately 1% of people aged 65 and older.1, 2 Clinically, it is characterized by severe motor symptoms including muscular rigidity, uncontrollable resting tremor, and bradykinesia, along with secondary symptoms such as postural instability, cognitive dysfunction (dementia, psychosis), sleep abnormalities, and mood disorders (depression, anxiety).1, 2 The pathophysiology of PD results from the progressive and selective loss of dopaminergic neurons in the substantia nigra pars compacta,3 with the consequent depletion of dopamine in its striatal projections, and other brainstem regions. This leads to disruption of the cerebral neuronal systems responsible for motor function.1, 4 In addition, the PD brain is characterized by the presence of cytoplasmic and neuritic fibrillar alpha-synuclein inclusions (known as Lewy bodies and Lewy neurites, respectively) in the surviving dopaminergic neurons and other affected areas of the CNS.1

The precise pathogenesis of the majority of PD cases is unclear, but genetic mutations in the gene for alpha-synuclein (A53T, A30P, and E46K)5, 6 and overexpression of alpha-synuclein gene have been associated with familial forms of PD.2 PD characterized by alpha-synuclein containing Lewy bodies accounts for >90% of sporadic Parkinsonian cases.2 The mechanism of alpha-synuclein-induced toxicity is still being investigated, but may be related to the propensity of normal alpha-synuclein and mutated forms to self-aggregate at higher concentrations, producing fibrils with amyloid-like cross-beta conformation.1 Zhang et al. propose that nigral neuronal damage may release aggregated alpha-synuclein into the substantia nigra, activating microglia and the subsequent production of pro-in­flammatory mediators and ROS (reactive oxygen species). These factors contribute to persistent and progressive nigral degeneration in PD.7

Animal models of PD are essential tools for identifying novel therapeutic targets and testing potential therapies. Until recently, the field has been dominated by toxin-based models.8, 9 These models are valuable for understanding what happens when nigrostriatal dopaminergic cells are lost, for testing dopamine replacement therapies, and for identifying interventions to reduce lesion size.9 Nevertheless, these approaches are valuable only when it is assumed that the mechanism of action of these toxins is germane to the pathophysiological process occurring in PD.9 But this is not necessarily true. Evidence exists that some of these toxins cause dopaminergic cell loss in humans (e.g. the mitochondrial toxin, MPTP) or increase the risk of PD after long-term exposure, but there is no clear evidence that the mechanisms are the same.9 As a result, these models do not display the full pathology and progression seen in PD.1 Schneider et al. have developed an in vitro model based on human progenitor cells.10 Their model convincingly shows the cytotoxicity of alpha-synuclein, although it too has limitations. Ethical concerns and technical hurdles still limit the derivation of these cells, and like the toxin-based models, they do not show the time-dependent pathogenesis characterized by PD.10

Misfolded alpha-synuclein proteins are converted into pathological oligomers and higher order aggregates that form fibrils and deposit into Lewy bodies and Lewy neurites in affected neurons of the PD brain.
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Misfolded alpha-synuclein proteins are converted into pathological oligomers and higher order aggregates that form fibrils and deposit into Lewy bodies and Lewy neurites in affected neurons of the PD brain. Several consequences of these fibrillar deposits of alpha-synuclein have been proposed and are indicated. (Figure adapted from reference #2)

Recchia et al. now describe and characterize an animal model that more faithfully reproduces alpha-synuclein-induced neurotoxicity and human PD pathology.1 Their model is based on the sterotaxic injection of the A30P mutated form of alpha-synuclein fused to a protein transduction domain (TAT) into the right substantia nigra pars compacta of rat.1 In their study, the infusion of TAT-alpha-synuclein A30P induced a significant loss in dopaminergic neurons (26%), which was followed by a time-dependent impairment of motor function.1 Compared to chemical neurotoxin-based animal models of PD, the alpha-synuclein-based PD animal model more clearly mimics the early stages and slow development of the human disease. Therefore, this model should prove valuable in evaluating specific aspects of PD pathogenesis in vivo and in devel­oping new therapeutic strategies.1


  1. Recchia, A. et al. (2008) Neurobiol. Dis. 30:8.
  2. Lee, V.M-Y. and J.Q. Trojanowski (2006) Neuron 52:33.
  3. Tanner, C.M. (1992) Occup. Med. 7:503.
  4. Dawson, T.M. and V.L. Dawson (2003) Science 302:819.
  5. Forman, M.S. et al. (2005) Neuron 47:479.
  6. Savitt, J.M. et al. (2006) J. Clin. Invest. 116:1744.
  7. Zhang et al. (2005) FASEB J. 19:533.This reference cites the use of R&D Systems products
  8. Dauer, W. and S. Przedborski (2003) Neuron 39:889.
  9. Chesselet, M-F. (2008) Exp. Neurol. 209:22.
  10. Schneider, B.L. et al. (2007) Hum. Mol. Genet. 16:651.This reference cites the use of R&D Systems products

This reference cites the use of R&D Systems products This symbol denotes references that cite the use of R&D Systems products.