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Project Summaries

Ataxia

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graphicWe follow a large cohort of patients with inherited spinocerebellar ataxia, about half of whom have no known basis for their disease. In addition, we and our clinical colleagues, Susan Perlman and Joanna Jen continue to see ataxia patients in the neurology clinic and are working on national collaborative efforts to identify potential therapies and advance clinical trials in this area. We have used microarrays to study a Friedreich’s Ataxia mouse model and patient fibroblasts and have recently made significant progress (Coppola et al. 2006). We are moving to creating in vitro models for rapid drug screening so as to identify new targets for the disease (Giovanni Coppola and Maren Engelhardt) and develop biomarkers that can be used to track disease progress and treatment

 

 

Autism

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graphicThe largest collection of well-characterized families with autism and related disorders is publicly available for any qualified researcher to use and study. This includes cell lines and an on-line phenotypic database. For more information see www.agre.org and www.cureautismnow.org Our own collaborative group has made significant progress in autism genetics, performing the largest genome scans in autism and confirming the first autism locus at genome-wide signficance (Yonan et al. 2003; Cantor et al. 2005). Our approach has focused on using endophenotypes such as sex, language and social cognition to increase power to detect autism related genetic risk factors (e.g. Alarcon et al. 2005; 2002; Chen et al. 2005; Stone et al. 2004).

We have developed a Center for Autism Research and Treatment at UCLA (www.autism.ucla.edu) under the STAART funding mechanism (www.nimh.nih.gov/autismiacc/staart.cfm). Dr. Geschwind and Dr. Marian Sigman co-direct this center (Dr. Sigman is PI of the NIMH grant).

 

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Cerebral Asymmetry

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The cerebral cortices are functionally and anatomically distinct. Although much is known with regards to the organization of the brain in the anterior-posterior and dorsal-ventral axes, little is known about the biological basis of cerebral asymmetry. Since asymmetry is fundamentally related to language functioning, the molecular basis of asymmetry development is fundamental to the organization of language in the human brain. Similarly, brain asymmetry may be disrupted in many neurodevelopmental disorders, such as autism and dyslexia or SLI. We are testing candidate genes involved in left-right asymmetry in other organ systems for asymmetric expression during human brain development (Abu Khalil et al. 2004) and using microarrays and other genomic screening techniques to identify novel asymmetrically expressed genes in human fetal brain.A powerful subtraction technique, representational difference analysis (RDA) is coupled to cDNA microarray analysis to permit high throughput screening of subtracted libraries (eg. Geschwind et al. 2001). We recently collaborated with Tao Sun in Chris Walsh’s laboratory to show the first evidence for transcriptional asymmetry in human fetal brain (Sun et al. 2005).

Funding: NIMH. Past funding from McDonnell-Pew foundation
 

Neural Stem Cell Biology

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graphicA collaborative effort between the Geschwind and Kornblum laboratories at UCLA. We used RDA and microarray technology to identify genes enriched in neural stem cell cultures, called neurospheres. This project is a first in this rapidly moving area and laid the groundwork for understanding the genetic basis of neural stem cell proliferation. A significant number of the genes enriched in neurospheres were also enriched in hematapoietic stem cells relative to whole bone marrow, suggesting a common genetic program (Geschwind et al. 2001; Terskikh et al. 2001). Data from the Geschwind et al. 2001 paper is available in the data section and protocols used are in the protocol section for download. We have now demonstrated that a subset of the genes identified by genomic screening using microarrays are involved in neural stem cell proliferation. Thus, we have moved from microarray to in vitro and in vivo functional assessment, providing a clear proof of principal for this approach, while identifying novel genes playing important roles in stem cell functions. Two of these genes, MELK and TOPK, are kinases involved in cell cycle regulation in neural stem cell and progenitors (Nakano et al. 2005; Dougherty et al. 2005).

 

 

Neurodegenerative Dementias and Fahr’s Disease

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graphicNeurodegenerative Dementias: FTD and AD

We believe that common mechanisms underlie the regional vulnerability observed in some neurodegenerative conditions, such as fronto-temporal dementia and the inherited ataxias. Understanding the factors that lead to this susceptibility will be important in truly understanding and producing more effective treatments for these conditions. We have taken an approach using animal models and genetic association in humans.  Representative publications include Geschwind et al. 2002; Nasreddine et al. 1999; Jackson et al. 2002.

 

Fahr’s Disease (Idiopathic Basal Ganglia Calcification)

Calcification within the basal ganglia is most often benign and related to advanced age.  However, when it is due to an infectious, toxic, metabolic or genetic disease, neurologic or psychiatric abnormalities are more likely to occur.  These abnormalities include:  dystonia, choreoathetosis, ataxia, tremor, parkinsonism, epilepsy, dementia, and schizophrenia-like psychosis.  When any clinical abnormalities occur, the term Fahr’s Disease, or idiopathic basal ganglia calcification (IBGC) may be used as a general description for the condition.  Several Fahr’s Disease pedigrees have been reported.