Parkin protects against mitochondrial toxins and beta-amyloid accumulation in skeletal muscle cells.
Mutations in the ubiquitin ligase-encoding Parkin gene have been implicated in the pathogenesis of autosomal recessive Parkinson disease. Outside of the central nervous system, Parkin is prominently expressed in skeletal muscle. We have found accumulations of Parkin protein in skeletal muscle biopsies taken from patients with inclusion body myositis, a degenerative disorder in which intramyofiber accumulations of the beta-amyloid peptide are pathognomonic. In comparing primary cultures of skeletal muscle derived from parkin knock-out and wild-type mice, we have found the absence of parkin to result in greater sensitivity to mitochondrial stressors rotenone and carbonyl cyanide 3-chlorophenylhydrazone, without any alteration in sensitivity to calcium ionophore or hydrogen peroxide. Utilizing viral expression constructs coding for the Alzheimer disease and inclusion body myositis-linked beta-amyloid precursor protein and for its metabolic byproducts A beta42 and C100, we found that parkin knock-out muscle cells are also more sensitive to the toxic effects of intracellular A beta. We also constructed a lentiviral system to overexpress wild-type Parkin and have shown that boosting the levels of parkin expression in normal skeletal muscle cultures provides substantial protection against both mitochondrial toxins and overexpressed beta-amyloid. Correspondingly, exogenous Parkin significantly lowered A beta levels. These data support the hypothesis that in myocytes parkin has dual properties in the maintenance of skeletal muscle mitochondrial homeostasis and in the regulation of A beta levels.
Rosen
Kenneth M
KM
Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135, USA. kenneth_rosen@cchcs.org
Veereshwarayya
Vimal
V
Moussa
Charbel E-H
CE
Fu
Qinghao
Q
Goldberg
Matthew S
MS
Schlossmacher
Michael G
MG
Shen
Jie
J
Querfurth
Henry W
HW
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D006835:Hydrazones / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D007476:Ionophores / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
D016229:Amyloid beta-Peptides; D006835:Hydrazones; D007328:Insulin; D007476:Ionophores; D012402:Rotenone; C070053:carbonyl 3-chlorophenylhydrazone; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D002118:Calcium