Abstract
Aggregates, a hallmark of most neurodegenerative diseases, may have different properties, and possibly different roles in neurodegeneration. We analysed ubiquitin-proteasome pathway functions during cytoplasmic aggregation in polyglutamine (polyQ) diseases, using a unique model of motor neuron disease, the SpinoBulbar Muscular Atrophy. The disease, which is linked to a polyQ tract elongation in the androgen receptor (ARpolyQ), has the interesting feature that ARpolyQ aggregation is triggered by the AR ligand, testosterone. Using immortalized motor neurons expressing ARpolyQ, we found that a proteasome reporter, YFPu, accumulated in absence of aggregates; testosterone treatment, which induced ARpolyQ aggregation, allowed the normal clearance of YFPu, suggesting that aggregation contributed to proteasome de-saturation, an effect not related to AR nuclear translocation. Using AR antagonists to modulate the kinetic of ARpolyQ aggregation, we demonstrated that aggregation, by removing the neurotoxic protein from the soluble compartment, protected the proteasome from an excess of misfolded protein to be processed.
| Original language | English |
|---|---|
| Pages (from-to) | 1099-1111 |
| Number of pages | 13 |
| Journal | Neurobiology of Aging |
| Volume | 28 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - Jul 2007 |
Fingerprint
Keywords
- Aggregation
- Androgen receptor
- Antiandrogen
- Inclusion
- Motor neuron diseases
- Neurodegeneration
- Polyglutamine diseases
- Proteasome
- Spinal and bulbar muscular atrophy
- Testosterone
ASJC Scopus subject areas
- Clinical Neurology
- Biological Psychiatry
- Developmental Neuroscience
- Neurology
- Psychology(all)
Cite this
Aggregation and proteasome : The case of elongated polyglutamine aggregation in spinal and bulbar muscular atrophy. / Rusmini, Paola; Sau, Daniela; Crippa, Valeria; Palazzolo, Isabella; Simonini, Francesca; Onesto, Elisa; Martini, Luciano; Poletti, Angelo.
In: Neurobiology of Aging, Vol. 28, No. 7, 07.2007, p. 1099-1111.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Aggregation and proteasome
T2 - The case of elongated polyglutamine aggregation in spinal and bulbar muscular atrophy
AU - Rusmini, Paola
AU - Sau, Daniela
AU - Crippa, Valeria
AU - Palazzolo, Isabella
AU - Simonini, Francesca
AU - Onesto, Elisa
AU - Martini, Luciano
AU - Poletti, Angelo
PY - 2007/7
Y1 - 2007/7
N2 - Aggregates, a hallmark of most neurodegenerative diseases, may have different properties, and possibly different roles in neurodegeneration. We analysed ubiquitin-proteasome pathway functions during cytoplasmic aggregation in polyglutamine (polyQ) diseases, using a unique model of motor neuron disease, the SpinoBulbar Muscular Atrophy. The disease, which is linked to a polyQ tract elongation in the androgen receptor (ARpolyQ), has the interesting feature that ARpolyQ aggregation is triggered by the AR ligand, testosterone. Using immortalized motor neurons expressing ARpolyQ, we found that a proteasome reporter, YFPu, accumulated in absence of aggregates; testosterone treatment, which induced ARpolyQ aggregation, allowed the normal clearance of YFPu, suggesting that aggregation contributed to proteasome de-saturation, an effect not related to AR nuclear translocation. Using AR antagonists to modulate the kinetic of ARpolyQ aggregation, we demonstrated that aggregation, by removing the neurotoxic protein from the soluble compartment, protected the proteasome from an excess of misfolded protein to be processed.
AB - Aggregates, a hallmark of most neurodegenerative diseases, may have different properties, and possibly different roles in neurodegeneration. We analysed ubiquitin-proteasome pathway functions during cytoplasmic aggregation in polyglutamine (polyQ) diseases, using a unique model of motor neuron disease, the SpinoBulbar Muscular Atrophy. The disease, which is linked to a polyQ tract elongation in the androgen receptor (ARpolyQ), has the interesting feature that ARpolyQ aggregation is triggered by the AR ligand, testosterone. Using immortalized motor neurons expressing ARpolyQ, we found that a proteasome reporter, YFPu, accumulated in absence of aggregates; testosterone treatment, which induced ARpolyQ aggregation, allowed the normal clearance of YFPu, suggesting that aggregation contributed to proteasome de-saturation, an effect not related to AR nuclear translocation. Using AR antagonists to modulate the kinetic of ARpolyQ aggregation, we demonstrated that aggregation, by removing the neurotoxic protein from the soluble compartment, protected the proteasome from an excess of misfolded protein to be processed.
KW - Aggregation
KW - Androgen receptor
KW - Antiandrogen
KW - Inclusion
KW - Motor neuron diseases
KW - Neurodegeneration
KW - Polyglutamine diseases
KW - Proteasome
KW - Spinal and bulbar muscular atrophy
KW - Testosterone
UR - http://www.scopus.com/inward/record.url?scp=34247365603&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34247365603&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2006.05.015
DO - 10.1016/j.neurobiolaging.2006.05.015
M3 - Article
C2 - 16781019
AN - SCOPUS:34247365603
VL - 28
SP - 1099
EP - 1111
JO - Neurobiology of Aging
JF - Neurobiology of Aging
SN - 0197-4580
IS - 7
ER -