title: Loss of Mfn2 results in progressive, retrograde degeneration of dopaminergic neurons in the nigrostriatal circuit.
abstract: Mitochondria continually undergo fusion and fission, and these dynamic processes play a major role in regulating mitochondrial function. Studies of several genes associated with familial Parkinson's disease (PD) have implicated aberrant mitochondrial dynamics in the disease pathology, but the importance of these processes in dopaminergic neurons remains poorly understood. Because the mitofusins Mfn1 and Mfn2 are essential for mitochondrial fusion, we deleted these genes from a subset of dopaminergic neurons in mice. Loss of Mfn2 results in a movement defect characterized by reduced activity and rearing. In open field tests, Mfn2 mutants show severe, age-dependent motor deficits that can be rescued with L-3,4 dihydroxyphenylalanine. These motor deficits are preceded by the loss of dopaminergic terminals in the striatum. However, the loss of dopaminergic neurons in the midbrain occurs weeks after the onset of these motor and striatal deficits, suggesting a retrograde mode of neurodegeneration. In our conditional knockout strategy, we incorporated a mitochondrially targeted fluorescent reporter to facilitate tracking of mitochondria in the affected neurons. Using an organotypic slice culture system, we detected fragmented mitochondria in the soma and proximal processes of these neurons. In addition, we found markedly reduced mitochondrial mass and transport, which may contribute to the neuronal loss. These effects are specific for Mfn2, as the loss of Mfn1 yielded no corresponding defects in the nigrostriatal circuit. Our findings indicate that perturbations of mitochondrial dynamics can cause nigrostriatal defects and may be a risk factor for the neurodegeneration in PD.
authors.affiliation: Division of Biology, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125, USA.
authors.forename: Anh H
authors.initials: AH
authors.lastname: Pham
authors.forename: Shuxia
authors.initials: S
authors.lastname: Meng
authors.forename: Quynh N
authors.initials: QN
authors.lastname: Chu
authors.forename: David C
authors.initials: DC
authors.lastname: Chan
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000235:genetics; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D017353:Gene Deletion; D057238:Growth Charts; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity / Q000235:genetics; D009069:Movement Disorders / Q000235:genetics; D010641:Phenotype; D012183:Retrograde Degeneration / Q000235:genetics*
chemical_list: D007980:Levodopa; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse