Huntington's disease (HD) pathology is well understood at a histological level but a comprehensive molecular analysis of the effect of the disease in the human brain has not previously been available. To elucidate the molecular phenotype of HD on a genome-wide scale, we compared mRNA profiles from 44 human HD brains with those from 36 unaffected controls using microarray analysis. Four brain regions were analyzed: caudate nucleus, cerebellum, prefrontal association cortex [Brodmann's area 9 (BA9)] and motor cortex [Brodmann's area 4 (BA4)]. The greatest number and magnitude of differentially expressed mRNAs were detected in the caudate nucleus, followed by motor cortex, then cerebellum. Thus, the molecular phenotype of HD generally parallels established neuropathology. Surprisingly, no mRNA changes were detected in prefrontal association cortex, thereby revealing subtleties of pathology not previously disclosed by histological methods. To establish that the observed changes were not simply the result of cell loss, we examined mRNA levels in laser-capture microdissected neurons from Grade 1 HD caudate compared to control. These analyses confirmed changes in expression seen in tissue homogenates; we thus conclude that mRNA changes are not attributable to cell loss alone. These data from bona fide HD brains comprise an important reference for hypotheses related to HD and other neurodegenerative diseases.
To test the hypotheses that mutant huntingtin protein length and wild-type huntingtin dosage have important effects on disease-related transcriptional dysfunction, we compared the changes in mRNA in seven genetic mouse models of Huntington's disease (HD) and postmortem human HD caudate. Transgenic models expressing short N-terminal fragments of mutant huntingtin (R6/1 and R6/2 mice) exhibited the most rapid effects on gene expression, consistent with previous studies. Although changes in the brains of knock-in and fulllength transgenic models of HD took longer to appear, 15-and 22-month CHL2 that the expression of full-length huntingtin transprotein might result in unique gene expression changes compared with those caused by the expression of an N-terminal huntingtin fragment, no discernable differences between full-length and fragment models were detected. In addition, very high correlations between the signatures of mice expressing normal levels of wild-type huntingtin and mice in which the wild-type protein is absent suggest a limited effect of the wild-type protein to change basal gene expression or to influence the qualitative disease-related effect of mutant huntingtin. The combined analysis of mouse and human HD transcriptomes provides important temporal and mechanistic insights into the process by which mutant huntingtin kills striatal neurons. In addition, the discovery that several available lines of HD mice faithfully recapitulate the gene expression signature of the human disorder provides a novel aspect of validation with respect to their use in preclinical therapeutic trials.
During sensory stimulation, visual cortical neurons undergo massive synaptic bombardment. This increases their input conductance, and action potentials mainly result from membrane potential fluctuations. To understand the response properties of neurons operating in this regime, we studied a model neuron with synaptic inputs represented by transient membrane conductance changes. We show that with a simultaneous increase of excitation and inhibition, the firing rate first increases, reaches a maximum, and then decreases at higher input rates. Comodulation of excitation and inhibition, therefore, does not provide a straightforward way of controlling the neuronal firing rate, in contrast to coding mechanisms postulated previously. The synaptically induced conductance increase plays a key role in this effect: it decreases firing rate by shunting membrane potential fluctuations, and increases it by reducing the membrane time constant, allowing for faster membrane potential transients. These findings do not depend on details of the model and, hence, are relevant to cells of other cortical areas as well.Key words: synaptic integration; membrane conductance; primary visual cortex; integrate-and-fire; intracellular recording; neural coding A growing number of laboratories record the membrane potential of cortical neurons in vivo [e.g., in the visual cortex (Pei et al., 1991;Ahmed et al., 1997;Azouz et al., 1997;Hirsch et al., 1998;Bringuier et al., 1999;Carandini and Ferster, 2000)], providing detailed insight into the way neurons operate within the functioning cortical network. These experiments showed that the barrage of synaptic input impinging on cortical neurons during sensory stimulation substantially increases the somatic input conductance (Borg-Graham et al., 1998;Hirsch et al., 1998). This, in turn, is expected to change the integration properties of the neurons (Bernander et al., 1991;Rapp et al., 1992;Destexhe and Paré, 1999;Rudolph and Destexhe, 2003). Moreover, these experiments revealed that the membrane potential strongly fluctuates [e.g., in response to visual stimuli (Anderson et al., 2000b)] but, on average, remains below firing threshold because it combines excitation and inhibition (Borg-Graham et al., 1998). Here we show that, under these conditions, both membrane potential fluctuations and firing rate evoked by simultaneously increasing excitation and inhibition are predicted to behave nonmonotonically. In particular, they can reach their maximal amplitude at moderate synaptic input rates and decrease for higher input rates.Neuronal firing rate is commonly assumed to be the carrier of information in the brain [but see also, e.g., for the visual cortex, Bair (1999)]. It is thus of utmost importance to understand how patterns of synaptic inputs determine the firing rate. To explain the irregular firing observed throughout the cortex (Softky and Koch, 1993), Newsome (1994, 1998) proposed that the firing rate of cortical neurons is essentially controlled by the size of membrane potential fluctuations: ...
Huntington's disease (HD), an incurable neurodegenerative disorder, has a complex pathogenesis including protein aggregation and the dysregulation of neuronal transcription and metabolism. Here, we demonstrate that inhibition of sirtuin 2 (SIRT2) achieves neuroprotection in cellular and invertebrate models of HD. Genetic or pharmacologic inhibition of SIRT2 in a striatal neuron model of HD resulted in gene expression changes including significant downregulation of RNAs responsible for sterol biosynthesis. Whereas mutant huntingtin fragments increased sterols in neuronal cells, SIRT2 inhibition reduced sterol levels via decreased nuclear trafficking of SREBP-2. Importantly, manipulation of sterol biosynthesis at the transcriptional level mimicked SIRT2 inhibition, demonstrating that the metabolic effects of SIRT2 inhibition are sufficient to diminish mutant huntingtin toxicity. These data identify SIRT2 inhibition as a promising avenue for HD therapy and elucidate a unique mechanism of SIRT2-inhibitor-mediated neuroprotection. Furthermore, the ascertainment of SIRT2's role in regulating cellular metabolism demonstrates a central function shared with other sirtuin proteins.cholesterol | Huntington's disease | metabolism | sirtuin | transcription factor SREBP-2
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