title: Proteasomal and autophagic degradative activities in spinal and bulbar muscular atrophy.
abstract: Spinal and bulbar muscular atrophy (SBMA or Kennedy's disease) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons in the bulbar region of the brain and in the anterior horns of the spinal cord. The disease has been associated to an expansion of a CAG triplet repeat present in the first coding exon of the androgen receptor (AR) gene. SBMA was the first identified member of a large class of neurodegenerative diseases now known as CAG-related diseases, which includes Huntington's disease (HD), several types of spinocerebellar ataxia (SCAs), and dentatorubral and pallidoluysian atrophy (DRPLA). The expanded CAG tract is translated to an aberrantly long polyglutamine tract (ARpolyQ) in the N-terminal region of the AR protein. The elongated polyQ tract seems to confer a neurotoxic gain-of-function to the mutant AR, possibly via the generation of aberrant conformations (misfolding). Protein misfolding is thought to be a trigger of neurotoxicity, since it perturbs a wide variety of motor neuronal functions. The first event is the accumulation of the ARpolyQ into ubiquitinated aggregates in a ligand (testosterone) dependent manner. The mutant ARpolyQ also impairs proteasome functions. The autophagic pathway may be activated to compensate these aberrant events by clearing the mutant ARpolyQ from motor neuronal cells. This review illustrates the mechanisms at the basis of ARpolyQ degradation via the proteasomal and autophagic systems.
authors.affiliation: Dipartimento di Endocrinologia, Fisiopatologia e Biologia Applicata, Università degli Studi di Milano, Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rusmini
authors.forename: Elena
authors.initials: E
authors.lastname: Bolzoni
authors.forename: Valeria
authors.initials: V
authors.lastname: Crippa
authors.forename: Elisa
authors.initials: E
authors.lastname: Onesto
authors.forename: Daniela
authors.initials: D
authors.lastname: Sau
authors.forename: Mariarita
authors.initials: M
authors.lastname: Galbiati
authors.forename: Margherita
authors.initials: M
authors.lastname: Piccolella
authors.forename: Angelo
authors.initials: A
authors.lastname: Poletti
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D055534:Bulbo-Spinal Atrophy, X-Linked / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine; D046988:Proteasome Endopeptidase Complex