Dysfunctional Dopaminergic Neurones in Mouse Models of Huntington's Disease: A Role for SK3 Channels

Huntington's disease (HD) is a late-onset fatal neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the gene coding for the protein huntingtin and is characterised by progressive motor, psychiatric and cognitive decline. We previously demonstrated that normal synaptic function in HD could be restored by application of dopamine receptor agonists, suggesting that changes in the release or bioavailability of dopamine may be a contributing factor to the disease process

MSH3 polymorphisms and protein levels affect CAG repeat instability in huntington's disease mice

Expansions of trinucleotide CAG/CTG repeats in somatic tissues are thought to contribute to ongoing disease progression through an affected individual's life with Huntington's disease or myotonic dystrophy. Broad ranges of repeat instability arise between individuals with expanded repeats, suggesting the existence of modifiers of repeat instability. Mice with expanded CAG/CTG repeats show variable levels of instability depending upon mouse strain. However, to date the genetic modifiers underlying these differences have not been identified. We show that in liver and striatum the R6/1 Huntington's disease (HD) (CAG)~100 transgene, when present in a congenic C57BL/6J (B6) background, incurred expansion-biased repeat mutations, whereas the repeat was stable in a congenic BALB/cByJ (CBy) background. Reciprocal congenic mice revealed the Msh3 gene as the determinant for the differences in repeat instability. Expansion bias was observed in congenic mice homozygous for the B6 Msh3 gene on a CBy background, while the CAG tract was stabilized in congenics homozygous for the CBy Msh3 gene on a B6 background. The CAG stabilization was as dramatic as genetic deficiency of Msh2. The B6 and CBy Msh3 genes had identical promoters but differed in coding regions and showed strikingly different protein levels. B6 MSH3 variant protein is highly expressed and associated with CAG expansions, while the CBy MSH3 variant protein is expressed at barely detectable levels, associating with CAG stability. The DHFR protein, which is divergently transcribed from a promoter shared by the Msh3 gene, did not show varied levels between mouse strains. Thus, naturally occurring MSH3 protein polymorphisms are modifiers of CAG repeat instability, likely through variable MSH3 protein stability. Since evidence supports that somatic CAG instability is a modifier and predictor of disease, our data are consistent with the hypothesis that variable levels of CAG instability associated with polymorphisms of DNA repair genes may have prognostic implications for various repeat-associated diseases

C9orf72-mediated ALS and FTD: multiple pathways to disease

The discovery that repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has revolutionized our understanding of these diseases. Substantial headway has been made in characterizing C9orf72-mediated disease and unravelling its underlying aetiopathogenesis. Three main disease mechanisms have been proposed: loss of function of the C9orf72 protein and toxic gain of function from C9orf72 repeat RNA or from dipeptide repeat proteins produced by repeat-associated non-ATG translation. Several downstream processes across a range of cellular functions have also been implicated. In this article, we review the pathological and mechanistic features of C9orf72-associated FTD and ALS (collectively termed C9FTD/ALS), the model systems used to study these conditions, and the probable initiators of downstream disease mechanisms. We suggest that a combination of upstream mechanisms involving both loss and gain of function and downstream cellular pathways involving both cell-autonomous and non-cell-autonomous effects contributes to disease progression

Altered dopaminergic function in a mouse model of Huntington's disease

In this work, we introduce multiplicative drift analysis as a suitable way to analyze the runtime of randomized search heuristics such as evolutionary algorithms. We give a multiplicative version of the classical drift theorem. This allows easier analyses in those settings where the optimization progress is roughly proportional to the current distance to the optimum. To display the strength of this tool, we regard the classical problem how the (1+1) Evolutionary Algorithm optimizes an arbitrary linear pseudo-Boolean function. Here, we first give a relatively simple proof for the fact that any linear function is optimized in expected time $O(n \log n)$, where $n$ is the length of the bit string. Afterwards, we show that in fact any such function is optimized in expected time at most {(1+o(1)) 1.39 \euler n\ln (n)}, again using multiplicative drift analysis. We also prove a corresponding lower bound of ${(1-o(1))e n\ln(n)}$ which actually holds for all functions with a unique global optimum. We further demonstrate how our drift theorem immediately gives natural proofs (with better constants) for the best known runtime bounds for the (1+1) Evolutionary Algorithm on combinatorial problems like finding minimum spanning trees, shortest paths, or Euler tours.Comment: Contains results from our GECCO 2010 and CEC 2010 conference pape

Fluid Biomarkers of Frontotemporal Lobar Degeneration

A timely diagnosis of frontotemporal degeneration (FTD) is frequently challenging due to the heterogeneous symptomatology and poor phenotype–pathological correlation. Fluid biomarkers that reflect FTD pathophysiology could be instrumental in both clinical practice and pharmaceutical trials. In recent years, significant progress has been made in developing biomarkers of neurodegenerative diseases: amyloid-β and tau in cerebrospinal fluid (CSF) can be used to exclude Alzheimer’s disease, while neurofilament light chain (NfL) is emerging as a promising, albeit nonspecific, marker of neurodegeneration in both CSF and blood. Gene-specific biomarkers such as PGRN in GRN mutation carriers and dipeptide repeat proteins in C9orf72 mutation carriers are potential target engagement markers in genetic FTD trials. Novel techniques capable of measuring very low concentrations of brain-derived proteins in peripheral fluids are facilitating studies of blood biomarkers as a minimally invasive alternative to CSF. A major remaining challenge is the identification of a biomarker that can be used to predict the neuropathological substrate in sporadic FTD patients