Journal Article

Pathological α-Synuclein Transmission Initiates Parkinson-like Neurodegeneration in Nontransgenic Mice

O'Brien, Patrick, Trojanowski, John Q., Lee, Virginia M.-Y., Carroll, Jenna, Zhang, Bin, Kehm, Victoria, Luk, Kelvin C.

2012

Overview

Parkinson's disease is characterized by abundant α-synuclein (α-Syn) neuronal inclusions, known as Lewy bodies and Lewy neurites, and the massive loss of midbrain dopamine neurons. However, a cause-and-effect relationship between Lewy inclusion formation and neurodegeneration remains unclear. Here, we found that in wild-type nontransgenic mice, a single intrastriatal inoculation of synthetic α-Syn fibrils led to the cell-to-cell transmission of pathologic α-Syn and Parkinson's-like Lewy pathology in anatomically interconnected regions. Lewy pathology accumulation resulted in progressive loss of dopamine neurons in the substantia nigra pars compacta, but not in the adjacent ventral tegmental area, and was accompanied by reduced dopamine levels culminating in motor deficits. This recapitulation of a neurodegenerative cascade thus establishes a mechanistic link between transmission of pathologic α-Syn and the cardinal features of Parkinson's disease.

• Publisher: American Association for the Advancement of Science
• Subject: alpha-Synuclein - administration & dosage / alpha-Synuclein - chemistry / alpha-Synuclein - metabolism / Animals / Biological and medical sciences / Brain / Cells, Cultured / Central nervous system diseases / Corpus Striatum - drug effects / Corpus Striatum - metabolism / Corpus Striatum - pathology / Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases / Dopamine / Dopaminergic Neurons - drug effects / Dopaminergic Neurons - metabolism / Dopaminergic Neurons - pathology / Formations / Hemispheres / Injections / Inoculation / Lewy Bodies - drug effects / Lewy Bodies - metabolism / Lewy Bodies - pathology / Medical sciences / Mice / Motors / Nervous system diseases / neurites / Neurodegenerative diseases / Neurology / Neurons / Parkinson disease / Parkinsonian Disorders - metabolism / Parkinsonian Disorders - pathology / Pathology / Protein Folding / Protein Transport / Proteins / Recombinant / Recombinant Proteins - administration & dosage / Recombinant Proteins - chemistry / Recombinant Proteins - metabolism / Substantia Nigra - drug effects / Substantia Nigra - metabolism / Substantia Nigra - pathology / Synaptic transmission / toxicity