Huntington’s disease (HD) is a late-onset and progressive neurodegenerative disorder that is caused by aggregation of mutant huntingtin protein which contains expanded-polyglutamine. which is an important factor for vesicle trafficking in the neuronal cells [12]. Htt also binds to repressor element 1 transcription factor/neuron restrictive silencer factor (REST/NRSF) which is involved in transcriptional repression [13]. In the huntingtin knockout mice study wild-type Htt is suggested to have an anti-apoptotic function in embryonic development [14]. In contrast to normal Htt mHtt has longer polyQ (>36) stretch in N-terminus. The length of polyQ stretch shows inverse correlation with the onset of symptom [1]. Recent study suggested that the number of polyQ tract in mHtt is implicated in flexibility which is required for close proximity between N17 (the first 17 amino acids of Htt) and proline-rich domain [15]. N17 and proline-rich domain have opposite effects on mHtt aggregation [16 17 The deletion of proline-rich domain leads to a rapid transition into aggregates in contrast the deletion of N17 domain decreases the mHtt aggregation [18]. It seems that the proline-rich domain prevents polyQ aggregation through inhibition of N17 at proximal position. When the flexibility of polyQ tract is reduced because of long polyQ length N17 is critical to induce mHtt aggregation. In the formation of protein Anacetrapib aggregation different threshold of polyQ length may be determined by different intradomain composition of disease protein in several types of polyQ disorders. The expanded polyQ-tract containing mHtt is easily misfolded and tends to self-aggregation [19]. It leads to formation of a toxic soluble oligomer and gradually accumulates into intracellular aggregates consisting of insoluble β-sheet rich amyloid deposits [20]. Previous studies have shown that mHtt aggregates are detected earlier than pathogenic symptoms in human patients and mouse model of HD [10]. It is doubtful that mHtt aggregates could induce the degeneration of neuron. A number of studies suggest that insoluble aggregates seem to play a protective role leading to autophagy-mediated clearance [21 22 Moreover R6/2 chimera and shortstop stain of YAC128 HD mouse models show no correlation of mHtt inclusion and pathogenic phenotype [23 24 Although there are still controversies which one is more toxic between soluble oligomer and insoluble aggregates the contributions of both putative toxic insults on HD are Rabbit polyclonal to LRRC15. reported. Thus it would be Anacetrapib better therapeutic direction to cope with misfolded monomer which inhibits aggregation with itself. THE MOLECULAR PATHOGENESIS OF MHTT IN HD Although mHtt has similar expression and distribution with normal Htt protein in HD patient toxicity of mHtt is region-specific especially striatum and cerebral cortex are vulnerable regions. Only a single report explains the striatum-specific neuronal degeneration resulting from mHtt sumoylation by Rhes (Ras homologue enriched in striatum) [25]. A prominent pathological feature of HD is accumulation of mHtt aggregates in neurons. mHtt is toxic to cells by affecting transcription mitochondrial function synaptic transmission and axonal transport (Fig. 1) [10]. mHtt interacts aberrantly and sequesters with many other cellular proteins into nuclear aggregates and cytoplasmic inclusion. Fig. 1 Potential molecular pathogenesis of toxicity of mHtt aggregates. Mutant huntingtin may affect the aberrant interaction with or sequester transcription factors leading to transcriptional dysregulation of many genes. Moreover mutant huntingtin causes defects Anacetrapib … In HD patients and mouse models of HD transcriptional dysregulation is an early feature in pathogenic mechanism. The transcriptions of key neuronal genes are progressively repressed by sequestering selective transcription factors and co-activator including cAMP response element binding protein (CREB) binding protein (CBP) TATA-binding protein (TBP) p53 SP1 and TAFII-130 into aggregates of mHtt [26 27 28 The mHtt also loses its ability to retain of cytoplasmic REST/NRSF leading to transcriptional Anacetrapib repression of neuron restrictive silencing element (NRSE) containing gene such as brain-derived neurotrophic factor (BDNF) [13 29 Nuclear localized REST/NRSF controls transcriptional repression of NRSE containing target genes through recruitment of co-repressor mSin3a HDAC1 and HDAC2. Consistent with microarray data ChIP-seq analysis.