Huntington’s disease

Huntington’s disease (HD) is a genetic neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene, which encodes an abnormally long polyglutamine repeat (polyQ) in the huntingtin protein (HTT). HD is inherited in an autosomal dominant manner, with age-dependent penetrance. Clinically, the disease is characterized by progressive motor dysfunction, cognitive decline, and psychiatric disturbances.1
It is widely accepted the involvement of mitochondrial dysfunctions and bioenergetic defects in HD and neurodegenerative diseases in general.2   The aim of this work is to investigate the effects of the fatty acid β-oxidation inhibitor Etomoxir on in vitro and in vivo model of HD. This compound interferes with mitochondria by irreversible inhibition of carnitine palmitoyltransferase-1 (CPT-1), the enzyme that catalyzes the first step in long-chain fatty acid import into mitochondria.3
In order to study the biological activity in vitro, Etomoxir was tested on mouse embryonic fibroblast cell line (NIH 3T3) and on striatal murine cell lines expressing HTT wild-type (STHdhQ7/7) and HTT mutated gene (STHdhQ109/109). Subsequently, it was evaluated the ability of Etomoxir to interfere with polyQ expression in STHdhQ109/109 cell line, following a 72h treatment.             Finally it was investigated the effect of Etomoxir on neuronal dysfunctions induced by mutant polyQ in transgenic C.elegans (fig.3). In such strain were expressed the first 57 aminoacids of human HTT containing expanded polyQ fused to fluorescent marker proteins in the six mechanosensory neurons. The increased polyQ expansion leads to a significant mechanosensory defective (Mec) phenotype in this strain.4
Our data showed that Etomoxir didn’t interfere with fibroblastic and neuronal proliferation, it was able to decrease PolyQ expression in HD cellular model and it rescued mechanosensorial dysfunction phenotypes induced by mutant polyQ in transgenic C.elegans.

The tripeptide glycine-proline-glutamate (GPE) is the naturally cleaved N-terminal tripeptide of insulin-like growth factor-1 (IGF-1) in brain tissues by an acid protease. Although GPE does not bind to IGF-1 receptors and its mode of action is not clear, in vitro studies have demonstrated its ability to stimulate acetylcholine and dopamine release, as well as to protect neurones from diverse induced brain injures. More importantly, GPE has been shown to have potent neuroprotective effects in numerous animal models of hypoxic-ischemic brain injury and neurodegenerative diseases such as Parkinsons, Alzheimers and Huntingtons diseases. As a consequence, GPE was suggested to be a potential target for the rational design of neuroprotective agents. Unfortunately, the use of GPE as a therapeutic agent is limited because of its unfavorable biochemical and pharmacokinetic properties. This review will focus on structural modifications performed on the GPE molecule in order to obtain bioactive analogues with increased pharmacokinetic profile useful for the treatment of central nervous system (CNS) injures and neurodegenerative disorders.

Objective: To determine whether Huntington disease (HD) mutation carriers have motor symptoms (complaints) when definite motor onset (motor phenoconversion) is diagnosed and document differences between the groups with and without unawareness of motor signs. Methods: We analyzed data from 550 HD mutation carriers participating in the multicenter PREDICT-HD Study followed through the HD prodrome. Data analysis included demographics, the Unified Huntington's Disease Rating Scale (UHDRS) and the Participant HD History of symptoms, self-report of progression, and cognitive, behavioral, and imaging measures. Unawareness was identified when no motor symptoms were self-reported but when definite motor HD was diagnosed. Results: Of 38 (6.91%) with onset of motor HD, almost half (18/38 5 47.36%) had no motor symptoms despite signs of disease on the UHDRS motor rating and consistent with unawareness. A group with motor symptoms and signs was similar on a range of measures to the unaware group. Those with unawareness of HD signs reported less depression. Patients with symptoms had more striatal atrophy on imaging measures. Conclusions: Only half of the patients with newly diagnosed motor HD had motor symptoms.

Guidelines recommend that predictive genetic testing for
Huntington disease (HD) should be deferred until the age of
majority (18 years in most countries). However, opposition
to these guidelines exists, with some professionals arguing
that testing may be beneficial for young people, and should
be considered much earlier. Empirical evidence is unable to
substantiate either position. We aimed to (1) explore the
experience of predictive genetic testing for HD from the
young person’s perspective and to (2) document the impact
that testing has upon various aspects of young people’s lives.
Eight young people who had undergone predictive genetic
testing for HD were interviewed. They ranged in age from 17
to 25 years at the time of their test. Four were female and two
had received a gene-positive test result. Interviews were
taped, transcribed and analyzed thematically. Three themes
emerged related to the time before the test was performed:
‘‘Living as though gene-positive,’’ ‘‘Risk behaviors,’’ and
‘‘Complex pasts.’’ Two themes emerged related to the time
after testing: ‘‘Identity difficulties’’ and ‘‘Living again.’’ When
the young people spoke about their experiences of predictive
testing, they placed these within a broader context of
growing up in a family affected by HD. For some of the
young people, uncertainty about their genetic status
constituted a barrier in their lives and prevented them from
moving forward. Testing alleviated these barriers in some
cases and helped them to move forward and make signi-
ficant behavioral changes. Not one of the young people
interviewed regretted undergoing predictive testing.

Objective: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. Methods: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression. Results: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele. Conclusions: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors. Neurology ® 2012;78:690–695 GLOSSARY HD Huntington disease. Huntington disease (HD) is a neurodegenerative disorder with motor impairment, cognitive decline, and psychiatric manifestations 1,2 caused by an expanded CAG trinucleotide repeat (35 CAGs) in the gene encoding huntingtin. The expansion shows a very strong negative correlation with age at onset of motor signs. 3–7 Although the dominant inheritance pattern of HD indicates that one expanded allele is sufficient to trigger the disorder, polymorphism of the normal allele CAG repeat (i.e., the number of consecutive CAGs in the nonexpanded allele; 36 CAGs) has been suggested in some but not all studies to influence the timing of onset of disease manifestations. 6 –9 Recently, an interaction of the expanded and normal allele was reported in a large study to modify age at onset based upon motor signs, cognitive change, and behavioral manifestations. 10 Counterintuitively, longer normal alleles (e.g., 30 CAGs) seemingly delayed age at onset of subjects with longer expanded CAG alleles (e.g., 50 CAGs). 10 This finding would have important implications for the precise molecular mechanism that initiates HD pathogenesis, as it would suggest that individual huntingtin molecules might physically interact, with a resultant alteration of the pathogenic potential of the expanded repeat. Similarly, if the normal allele can modify HD pathogenesis, it would provide a potential Authors' affiliations are provided at the end of the article. Coinvestigators and Contributors are listed on the Neurology Web site at www.neurology.org.

Huntington's disease (HD) is a fatal degenerative autosomal dominant neuropsychiatric disease that causes neuronal death and is characterized by progressive striatal and then widespread brain atrophy. Brain-derived neurotrophic factor (BDNF) is a lead candidate for the treatment of HD, as it has been shown to prevent cell death and to stimulate the growth and migration of new neurons in the brain in transgenic mouse models. BDNF levels are reduced in HD post-mortem human brain. Previous studies have shown efficacy of MSC/BDNF using
murine MSCs, and the present study used human MSCs to advance the therapeutic potential of the MSC/BDNF platform for clinical application. Double-blinded studies were performed to examine the effects of intrastriatally transplanted human MSC/BDNF on disease progression in two strains of immune suppressed HD transgenic mice: YAC128 and R6/2. MSC/BDNF treatment decreased striatal atrophy in YAC128 mice. MSC/BDNF treatment also significantly reduced anxiety as measured in the open field assay. Both MSC and MSC/BDNF treatments induced a significant increase in neurogenesis-like activity in R6/2 mice. MSC/BDNF treatment also increased the mean lifespan of the R6/2 mice. Our  genetically modified MSC/BDNF cells set a precedent for stem cell-based neurotherapeutics and could potentially be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis, Alzheimer's disease, and some forms of Parkinson's disease. These cells provide a platform delivery system for future studies involving corrective gene editing strategies.

Corticostriatal atrophy is a cardinal manifestation of Huntington's disease (HD). However, the mechanism(s) by which mutant hun-tingtin (mHTT) protein contributes to the degeneration of the corticostriatal circuit is not well understood. We recreated the corticostriatal circuit in microfluidic chambers, pairing cortical and striatal neurons from the BACHD model of HD and its WT control. There were reduced synaptic connectivity and atrophy of striatal neurons in cultures in which BACHD cortical and striatal neurons were paired. However, these changes were prevented if WT cortical neurons were paired with BACHD striatal neurons; synthesis and release of brain-derived neurotrophic factor (BDNF) from WT cortical axons were responsible. Consistent with these findings, there was a marked reduction in anterograde transport of BDNF in BACHD cortical neurons. Subunits of the cytosolic chap-eronin T-complex 1 (TCP-1) ring complex (TRiC or CCT for chaper-onin containing TCP-1) have been shown to reduce mHTT levels. Both CCT3 and the apical domain of CCT1 (ApiCCT1) decreased the level of mHTT in BACHD cortical neurons. In cortical axons, they normalized anterograde BDNF transport, restored retrograde BDNF transport, and normalized lysosomal transport. Importantly, treating BACHD cortical neurons with ApiCCT1 prevented BACHD striatal neuronal atrophy by enhancing release of BDNF that subsequently acts through tyrosine receptor kinase B (TrkB) receptor on striatal neurons. Our findings are evidence that TRiC reagent-mediated reductions in mHTT enhanced BDNF delivery to restore the trophic status of BACHD striatal neurons.

Although the Unified Huntington's Disease Rating Scale (UHDRS) is widely used in the assessment of Huntington disease (HD), the ability of individual items to discriminate individual differences in motor or behavioral manifestations has not been extensively studied in HD gene expansion carriers without a motor-defined clinical diagnosis (i.e., prodromal-HD or prHD). To elucidate the relationship between scores on individual motor and behavioral UHDRS items and total score for each subscale, a non-parametric item response analysis was performed on retrospective data from two multicentre, longitudinal studies. Motor and Behavioral assessments were supplied for 737 prHD individuals with data from 2114 visits (PREDICT-HD) and 686 HD individuals with data from 1482 visits (REGISTRY). Option characteristic curves were generated for UHDRS subscale items in relation to their subscale score. In prHD, overall severity of motor signs was low and participants had scores of 2 or above on very few items. In HD, motor items that assessed ocular pursuit, saccade initiation, finger tapping, tandem walking, and to a lesser extent saccade velocity, dysarthia, tongue protrusion, pronation/supination, Luria, bradykinesia,