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Introduction:

    Dr. Paisan-Ruiz’s laboratory at Icahn School of Medicine at Mount Sinai focuses on elucidating and understanding the molecular basis underlying and contributing to movement disorders such as Parkinson’s disease (PD), parkinsonian-like syndromes, and essential tremor (ET). To accomplish this, Paisan-Ruiz’s laboratory employs a variety of molecular biology techniques, such as genome-wide linkage analyses to identify disease-associated loci and whole exome sequencing approaches to identify disease-causing mutations. Worldwide clinical collaborators, who are responsible for patients recruitment and patient phenotypic examination, are also working with us to accomplish this ambitious goal. These analyses are of utmost importance for movement disorder research since gene discovery leads directly to model systems, a better understanding of disease pathogenesis, and novel targets for drug development.
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enetic studies in movement disorders have demonstrated their success in the discovery of underlying pathologic processes and have helped researchers to understand both disease manifestations and progression. The identification of genetic factors underlying, and contributing to, the development of movement disorders provides a powerful tool for understanding their associated pathology, and opens up new avenues for future investigations within the field of movement disorder research.
    Our laboratory has shown remarkable success in the identification of disease-associated genes for several movement disorders including PD, parkinsonism, and neurodegeneration with brain iron accumulation (NBIA). More recently, by using a combination of detailed phenotyping, homozygosity mapping, whole exome sequencing, and candidate gene analyses, we have identified the first pathogenic mutation in the gene that encodes for synaptojanin 1, which is known to play an important role in the regulation of neurotransmitter vesicles trafficking at synapses,in a family featuring early-onset parkinsonism. We were also able to show that the mutation identified in our patients impairs certain functions of the protein, leading to novel insights into the disease pathogenesis. Please follow the following link for more information about this recent and exciting finding. New genes have also been identified for both autosomal recessive and autosomal dominant myoclonic epilepsy (see selected publications for more details).
  To directly explore the molecular and cellular mechanisms by which abnormal the genes identified lead to  PD, ET, and related disorders, Paisan-Ruiz’s team also characterizes the function of normal versus disease-associated mutant proteins in the zebrafish central nervous system. The emerging literature on the genetics of zebrafish models provides relevant evidence that their cellular and pathological events can be highly applicable to the pathophysiology of human disorders. Despite its evolutionary distance, several hundred millions years, from mammals, the zebrafish genome is remarkably similar to the human genome. The catecholaminergic systems including dopamine releasing neurons and a set of dopamine receptors has recently been described and genetically analyzed in zebrafish. Two of the most important advances made possible by the zebrafish are the ability to knock down the function of almost any gene by using morpholinos and the ability to determine the tissue localization of any gene of interest. The optical transparency of zebrafish embryos makes them an excellent system in which to express fluorescent proteins to label neurons for morphological analysis and localizations. The knock-down of several movement disorder genes in the zebrafish central nervous system have already demonstrated that its functional losses result in neurodegeneration. This approach enables a relatively high throughput means of studying a protein’s function and can be exploited to identify signaling pathways to advance in the development of novel and more efficient therapeutic approaches. Novel insights into the etiology and treatment will be achieved by the use of zebrafish models, facilitating subsequent basic and clinical research.

Ongoing Projects:
 
1. Genetic Analyses in Late-Onset Parkinson’s Disease
This project basically consists of identifying new genes or genetic factors associated with the development of late-onset PD. For this approach, we have collected hundreds of DNA samples from patients featuring late-onset PD and whole exome sequencing (WES) is currently being performed. One of our strength for this project is the use of a very well clinically characterized and ethnically homogeneous DNA sample collection.
2. Clinical and Genetic Studies in Essential Tremor

    The long-term goal of this project is to gain insights into the etiology of essential tremor (ET), which remains poorly understood, by determining novel gene mutations underlying tremor. All patients to be examined here are from the same isolated geographical region in the North of Spain and are subject to a continuing full clinical analysis.  Since conventional linkage analyses performed in ET have failed to identify causal genes, WES is being used for this approach.

3. Gene Discovery for Complex Movement Disorders (CMDs)
CMDs defined as disorders in which patients are affected by more than one movement disorder (such as parkinsonism and dystonia, or myoclonus and tremor), are a continuing challenge for diagnosis and treatment. We believe that intense study of these disorders represents a powerful approach to elucidate disease mechanism for both CMD and for more common disorders such as Parkinson’s disease, and will lead to improvements in both diagnoses and treatments. Linkage analyses, candidate gene screening, and WES approaches are being used to attain this aim. 4. Zebrafish Models of Complex Movement Disorder
    The phenotypic and etiologic heterogeneity in patients with CMDs is quite striking, presenting a significant challenge for treatment. In an attempt to identify molecular network(s) associated with these CMDs and to facilitate novel treatments, the phenotypic implications and functional consequences of the newly identified genes are being examined in the zebrafish central nervous system. The availability of morpholinos, which transiently and reversibly suppress specific parts of the genome, provides a unique tool to investigate the brain mechanisms driving the pathogenesis of neurological diseases.

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