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

Aggregation and proteasome: the case of elongated polyglutamine aggregation in spinal and bulbar muscular atrophy / P. Rusmini, D. Sau, V. Crippa, I. Palazzolo, F. Simonini, E. Onesto, L. Martini, A. Poletti. - In: NEUROBIOLOGY OF AGING. - ISSN 0197-4580. - 28:7(2007), pp. 1099-1111.

Aggregation and proteasome: the case of elongated polyglutamine aggregation in spinal and bulbar muscular atrophy

P. Rusmini;D. Sau;V. Crippa;I. Palazzolo;F. Simonini;E. Onesto;L. Martini;A. Poletti
2007

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
Aggregation; Androgen receptor; Antiandrogen; Inclusion; Motor neuron diseases; Neurodegeneration; Polyglutamine diseases; Proteasome; Spinal and bulbar muscular atrophy; Testosterone
Settore BIO/13 - Biologia Applicata
NEUROBIOLOGY OF AGING
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/28565
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