Huntington s disease(HD) insolubility. Administration of cystamine, a transglutaminase inhibitor, reduces the To date, 10 neurological diseases, including aggregate formation, retarding the Huntington's and several ataxias, are caused development of neurological phenotype and by the lengthening of glutamine(@) tracts in prolonging the life span of brain cells in various proteins with no obvious functional or transgenic mouse models evolutionary relationships. This phenomenon results from a mutation involving a CA e corresponding ge though the Q expansions arise in proteins, the diseases share three striking Image removed due to copyright considerations features See Figure 1 in Tarlac, V and Storey, E. 2003. Role of (1) The existence of a stretch of proteolysis in polyglutar 35-45 glutamine residues in the Res.74:406-416. mutant protein. (2) The Q-expanded proteins are expressed in many tissues pathology is largely restricted to neurons (3) The Q-expanded protei Several hypotheses have been advanced to fragments thereof form explain why expanded glutamine regions cause inclusions that also neuronal degeneration The polyQ fragments may form cationic channels in membranes Although they differ in their clinical Intranuclear aggregation may presentation and neuropathological profile, the interfere with the function of patients display different combinations of transcription factors that also motor, psychiatric, cognitive, an contain glutamine tracts, thereby symptoms causing misregulation In Huntingtons, the disease is caused by a mutation in the gene encoding for Huntingtin (a protein of unknown function, although has neurodegenerative diseases may been recently implicated in the control of gene result from impaired proteolysis transcription). Huntingtin has been found to either because the protein/fragment ubiquitinated and also interacts with the becomes inherently difficultto E2-25 grade or bed In principle, the poly Q disease result from functional inactivation eof cac overwhelming and inhibiting the ubiquitin-proteasome pathw protein. However, expression of polyQ sequences attached to other proteins(such as As we have seen for other neurodegenerative GFP)can cause cell death. Thus, it seems tha diseases, evidences point out to the possibility neurodegeneration is, in fact, a toxic manifestation of the expanded Q tract. Poly Q represent a means for the cell to effectively forms polar zippers (amyloid-like fibrils sequester toxic misfolded proteins, thereby consisting of B strands of the mutant protein shielding organelles from damage. In such that result in protein aggregation, in the form case. the inclusions would have a of intranuclear or cytoplasmic inclusions neuroprotective function. However, continued Transglutaminase-mediated cross-linking of production/accumulation of the aberrant glutamine in poly Q tracts to lysines in the proteins would, as in othe er neuro same or other proteins can account for both disease activate stress-related pathways the formation of inclusions and their which would finally end up in neuronalHuntington’s disease (HD) To date, 10 neurological diseases, including Huntington’s and several ataxias, are caused by the lengthening of glutamine (Q) tracts in various proteins with no obvious functional or evolutionary relationships. This phenomenon results from a mutation involving a CAG repeat expansion in the corresponding genes. Even though the Q expansions arise in unrelated proteins, the diseases share three striking features: (1) The existence of a stretch of 35-45 glutamine residues in the mutant protein. (2) The Q-expanded proteins are expressed in many tissues, yet pathology is largely restricted to neurons. (3) The Q-expanded proteins or fragments thereof form nuclear inclusions that also contain ubiquitin, proteasomes and chaperones. Although they differ in their clinical presentation and neuropathological profile, the patients display different combinations of motor, psychiatric, cognitive, and sensory symptoms. In Huntington’s, the disease is caused by a mutation in the gene encoding for Huntingtin (a protein of unknown function, although has been recently implicated in the control of gene transcription). Huntingtin has been found to be ubiquitinated and also interacts with the ubiquitin-conjugating enzyme E2-25. In principle, the polyQ diseases could result from functional inactivation of each protein. However, expression of polyQ sequences attached to other proteins (such as GFP) can cause cell death. Thus, it seems that neurodegeneration is, in fact, a toxic manifestation of the expanded Q tract. PolyQ forms polar zippers (amyloid-like fibrils consisting of β strands of the mutant protein) that result in protein aggregation, in the form of intranuclear or cytoplasmic inclusions. Transglutaminase-mediated cross-linking of glutamine in polyQ tracts to lysines in the same or other proteins can account for both the formation of inclusions and their insolubility. Administration of cystamine, a transglutaminase inhibitor, reduces the aggregate formation, retarding the development of neurological phenotype and prolonging the life span of brain cells in transgenic mouse models. Image removed due to copyright considerations. See Figure 1 in Tarlac, V. and Storey, E. 2003. Role of proteolysis in polyglutamine disorders. J. Neurosci. Res. 74: 406-416. Several hypotheses have been advanced to explain why expanded glutamine regions cause neuronal degeneration: • The polyQ fragments may form cationic channels in membranes. • Intranuclear aggregation may interfere with the function of transcription factors that also contain glutamine tracts, thereby causing misregulation of gene expression. • PolyQ and several other neurodegenerative diseases may result from impaired proteolysis, either because the protein/fragment becomes inherently difficult to degrade or because it can end up overwhelming and inhibiting the ubiquitin-proteasome pathway. As we have seen for other neurodegenerative diseases, evidences point out to the possibility that intracellular protein inclusions could represent a means for the cell to effectively sequester toxic misfolded proteins, thereby shielding organelles from damage. In such case, the inclusions would have a neuroprotective function. However, continued production/accumulation of the aberrant proteins would, as in other neurodegenerative disease activate stress-related pathways which would finally end up in neuronal