Androgen receptor with elongated polyglutamine tract forms aggregates that alter axonal trafficking and mitochondrial distribution in motor neuronal processes.
The CAG/polyglutamine (polyGln)-related diseases include nine different members that together form the most common class of inherited neurodegenerative disorders; neurodegeneration is linked to the same type of mutation, found in unrelated genes, consisting of an abnormal expansion of a polyGln tract normally present in the wild-type proteins. Nuclear, cytoplasmic, or neuropil aggregates are detectable in CAG/polyGln-related diseases, but their role is still debated. Alteration of the androgen receptor (AR), one of these proteins, has been linked to spinal and bulbar muscular atrophy, an X-linked recessive disease characterized by motoneuronal death. By using immortalized motoneuronal cells (the neuroblastoma-spinal cord cell line NSC34), we analyzed neuropil aggregate formation and toxicity: green fluorescent protein-tagged wild-type or mutated ARs were cotransfected into NSC34 cells with a blue fluorescent protein tagged to mitochondria. Altered mitochondrial distribution was observed in neuronal processes containing aggregates; occasionally, neuropil aggregates and mitochondrial concentration corresponded to axonal swelling. Neuropil aggregates also impaired the distribution of the motor protein kinesin. These data suggest that neuropil aggregates may physically alter neurite transport and thus deprive neuronal processes of factors or components that are important for axonal and dendritic functions. The soma may then be affected, leading to neuronal dysfunctions and possibly to cell death.
Piccioni
Federica
F
Institute of Endocrinology, Centre of Excellence for the Study and Treatment of Neurodegenerative Diseases, University of Milan, Milano, Italy.
Pinton
Paolo
P
Simeoni
Silvia
S
Pozzi
Paola
P
Fascio
Umberto
U
Vismara
Guglielmo
G
Martini
Luciano
L
Rizzuto
Rosario
R
Poletti
Angelo
A
D000818:Animals; D001370:Axonal Transport; D016547:Kinesins / Q000032:analysis; D008928:Mitochondria / Q000648:ultrastructure*; D008959:Models, Neurological; D009046:Motor Neurons / Q000737:chemistry / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure*; D016501:Neurites / Q000648:ultrastructure; D019581:Neuropil / Q000737:chemistry / Q000166:cytology / Q000648:ultrastructure; D010455:Peptides / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics*; D014407:Tumor Cells, Cultured
D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine; D016547:Kinesins