The main histopathological feature of Huntington’s disease (HD) is the presence of protein aggregates that are gathered into inclusion bodies. So far the mechanisms that lead to inclusion formation as well as their role in the pathogenesis of HD are not totally understood. However, it is well established that inclusion bodies contain components of the ubiquitin-proteasome system. Accordingly, it has been postulated that impairment of this machinery can be one of the causes of this disorder. In this review, the authors summarize the state of current knowledge about this hypothesis.
Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S.2004. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature431:805−810.
2.
Bence NF, Sampat RM, Kopito RR. 2001. Impairment of the ubiquitinproteasome system by protein aggregation. Science292:1552−1555.
3.
Bennett EJ, Bence NF, Jayakumar R, Kopito RR. 2005. Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation. Mol Cell17:351−365.
4.
Bossy-Wetzel E, Schwarzenbacher R, Lipton SA. 2004. Molecular pathways to neurodegeneration. Nat Med10:S2−S9.
5.
Bowman AB, Yoo SY, Dantuma NP, Zoghbi HY. 2005. Neuronal dys-function in a polyglutamine disease model occurs in the absence of ubiquitin-proteasome system impairment and inversely correlates with the degree of nuclear inclusion formation. Hum Mol Genet14:679−691.
6.
Dantuma NP, Lindsten K, Glas R, Jellne M, Masucci MG. 2000. Short-lived green fluorescent proteins for quantifying ubiquitin/proteasome-dependent proteolysis in living cells. Nat Biotechnol18:538−543.
7.
Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, and others. 1997. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell90:537−548.
8.
DeMartino GN, Slaughter CA. 1999. The proteasome, a novel protease regulated by multiple mechanisms. J Biol Chem274:22123−22126.
9.
Díaz-Hernández M, Hernández F, Martin-Aparicio E, Gomez-Ramos P, Moran MA, Castano JG, and others. 2003. Neuronal induction of the immunoproteasome in Huntington’s disease. J Neurosci23:11653−11661.
10.
Díaz-Hernández M, Martin-Aparicio E, Avila J, Hernández F, Lucas JJ. 2004. Enhanced induction of the immunoproteasome by interferon gamma in neurons expressing mutant Huntingtin. Neurotox Res6:463−468.
11.
Díaz-Hernández M, Moreno-Herrero F, Gomez-Ramos P, Moran MA, Ferrer I, Baro AM, and others. 2004. Biochemical, ultrastructural, and reversibility studies on huntingtin filaments isolated from mouse and human brain. J Neurosci24:9361−9371.
12.
DiFiglia M, Sapp E, Chase K, Davies S, Bates G, Vonsattel J, and others. 1997. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science277:1990−1993.
13.
Ding Q, Lewis JJ, Strum KM, Dimayuga E, Bruce-Keller AJ, Dunn JC, and others. 2002. Polyglutamine expansion, protein aggregation, proteasome activity, and neural survival. J Biol Chem277:13935−13942.
14.
Fink AL. 1998. Protein aggregation: folding aggregates, inclusion bodies and amyloid. Fold Design3:R9−R23.
15.
Friedlander RM. 2003. Apoptosis and caspases in neurodegenerative diseases. N Engl J Med348:1365−1375.
16.
Goedert M, Spillantini MG, Davies SW. 1998. Filamentous nerve cell inclusions in neurodegenerative diseases. Curr Opin Neurobiol8:619–632.
17.
Heinsen H, Strik M, Bauer M, Luther K, Ulmar G, Gangnus D, and others. 1994. Cortical and striatal neurone number in Huntington’s disease. Acta Neuropathol (Berl)88:320−333.
18.
Hernández F, Díaz-Hernández M, Avila J, Lucas JJ. 2004. Testing the ubiquitin-proteasome hypothesis of neurodegeneration in vivo. Trends Neurosci27:66−70.
19.
Hershko A, Ciechanover A.1998The ubiquitin system. Annu Rev Biochem7:425−479.
20.
Hodgson JG, Agopyan N, Gutekunst CA, Leavitt BR, LePiane F, Singaraja R, and others. 1999. A YAC mouse model for Huntington’s disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron23:181−192.
21.
Huntington’s Disease Collaborative Research Group. 1993. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell72:971−983.
22.
Jana NR, Zemskov EA, Wang G, Nukina N.2001. Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release. Hum Mol Genet10:1049−1059.
23.
Keller JN, Hanni KB, Markesbery WR. 2000. Possible involvement of proteasome inhibition in aging: implications for oxidative stress. Mech Ageing Dev113:61−70.
24.
Keller JN, Huang FF, Markesbery WR. 2000. Decreased levels of proteasome activity and proteasome expression in aging spinal cord. Neuroscience98:149−156.
25.
Kim M, Lee HS, LaForet G, McIntyre C, Martin EJ, Chang P, and others. 1999. Mutant huntingtin expression in clonal striatal cells: dissociation of inclusion formation and neuronal survival by caspase inhibition. J Neurosci19:964−973.
26.
Kisselev AF, Kaganovich D, Goldberg AL. 2002. Binding of hydro-phobic peptides to several non-catalytic sites promotes peptide hydrolysis by all active sites of 20 S proteasomes. Evidence for peptide-induced channel opening in the alpha-rings. J Biol Chem277:22260–22270.
27.
Kopito RR. 2000. Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol10:524−530.
28.
Landles C, Bates GP. 2004. Huntingtin and the molecular pathogenesis of Huntington’s disease. Fourth in molecular medicine review series. EMBO Rep5:958−963.
29.
Levine MS, Klapstein GJ, Koppel A, Gruen E, Cepeda C, Vargas ME, and others. 1999. Enhanced sensitivity to N-methyl-D-aspartate receptor activation in transgenic and knockin mouse models of Huntington’s disease. J Neurosci Res58:515−532.
30.
Lindsten K, Dantuma NP. 2003. Monitoring the ubiquitin/proteasome system in conformational diseases. Ageing Res Rev2:433−449.
31.
Lindsten K, Menendez-Benito V, Masucci MG, Dantuma NP. 2003. A transgenic mouse model of the ubiquitin/proteasome system. Nat Biotechnol21:897–902.
32.
Martin-Aparicio E, Yamamoto A, Hernández F, Hen R, Avila J, Lucas JJ. 2001. Proteasomal-dependent aggregate reversal and absence of cell death in a conditional mouse model of Huntington’s disease. J Neurosci21:8772−8781.
33.
McGuire MJ, McCullough ML, Croall DE, DeMartino GN. 1989. The high molecular weight multicatalytic proteinase, macropain, exists in a latent form in human erythrocytes. Biochim Biophys Acta995:181−186.
34.
Morton AJ, Faull RL, Edwardson JM. 2001. Abnormalities in the synaptic vesicle fusion machinery in Huntington’s disease. Brain Res Bull56:111−117.
35.
Nakamura K, Jeong SY, Uchihara T, Anno M, Nagashima K, Nagashima T, and others. 2001. SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet10:1441−1448.
36.
Neefjes J, Dantuma NP. 2004. Fluorescent probes for proteolysis: tools for drug discovery. Nat Rev Drug Discov3:58−69.
37.
Poirier MA, Li H, Macosko J, Cai S, Amzel M, Ross CA. 2002. Huntingtin spheroids and protofibrils as precursors in polygluta-mine fibrilization. J Biol Chem277:41032−41037.
38.
Quinn N, Schrag A.1998. Huntington’s disease and other choreas. J Neurol245:709−716.
39.
Ross CA. 1997. Intranuclear neuronal inclusions: a common pathogenic mechanism for glutamine-repeat neurodegenerative diseases?Neuron19:1147−1150.
40.
Ross CA. 2002. Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington’s disease and related disorders. Neuron35:819−822.
41.
Ross CA, Poirier MA. 2004. Protein aggregation and neurodegenerative diseases. Nat Med10:S10−S17.
42.
Saudou F, Finkbeiner S, Devys D, Greenberg ME. 1998. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell95:55−66.
43.
Scherzinger E, Lurz R, Turmaine M, Mangiarini L, Hollenbach B, Hasenbank R, and others. 1997. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell90:549−558.
44.
Seo H, Sonntag KC, Isacson O.2004. Generalized brain and skin proteasome inhibition in Huntington’s disease. Ann Neurol56:319−328.
45.
Sherman MY, Goldberg AL. 2001. Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases. Neuron29:15–32.
46.
Stack JH, Whitney M, Rodems SM, Pollok BA. 2000. A ubiquitin-based tagging system for controlled modulation of protein stability. Nat Biotechnol18:1298–12302.
Venkatraman P, Wetzel R, Tanaka M, Nukina N, Goldberg AL. 2004. Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins. Mol Cell14:95–104.
Waelter S, Boeddrich A, Lurz R, Scherzinger E, Lueder G, Lehrach H, and others. 2001. Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. Mol Biol Cell12:1393−1407.
51.
Yamamoto A, Lucas JJ, Hen R.2000. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington’s disease. Cell101:57−66.
52.
Zoghbi HY, Orr HT. 2000. Glutamine repeats and neurodegeneration. Annu Rev Neurosci23:217−247.
53.
Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, and others. 2001. Loss of Huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science293:493−498.
