Towards Deciphering Parkinsonism-Associated Pathogenesis
My research laboratory focuses on the identification and functional characterization of genes underlying neurodegenerative diseases, with special focus on Parkinson’s disease (PD) and parkinsonism+ syndromes. For this, my lab collaborates closely with physicians expert in movement disorders and other neurodegenerative diseases who provide us with DNA material from affected patients and their relatives, which we use to determine the genetic defects underlying and/or contributing to disease pathogenesis. Accordingly, my team employs cutting-edge molecular techniques, including genome-wide genotyping arrays, whole genome sequencing with short and long reads, and transcriptome sequencing, as well as performs functional assays in cellular and animal (zebrafish) models to investigate the functional properties of the impaired genes.
The applications of machine learning (ML) techniques in genomics are endless and are changing the field of precision medicine. Thus, my lab is beginning to use a combination of statistical and ML approaches to integrate health data types, risk factors, and other types of omics data in order to predict an individual’s probability of developing parkinsonism and to interpret how genetic variations might affect crucial biological processes. We believe that a better understanding of the genomic variation underlying disease will be reached by the integration and interpretation of multi-omics data.
A large part of my lab is working on the genetic architecture and characterization of parkinsonism+ syndromes that we define as those manifesting with parkinsonism (rigidity, tremor, bradykinesia, postural instability) accompanied by other neurological manifestation (i.e. intellectual disability, epilepsy, neuropathy). These syndromes are rare and usually studied much less than other common forms of parkinsonism. They are often caused by mutations in one gene, which makes determining the disease cause less complicated. Discovering the gene involved in rare and complex disease form and its function has been shown to shed light on the function of other gene products that interact with it, meaning that disease genes involved in complex forms of parkinsonism can also impact our understanding of common PD. Their identification helps us understand both normal and diseased brain functions. As an example, I found our discovery of synj1 mutations in families with parkinsonism and epilepsy very exciting. LRRK2, a gene involved in common forms of PD and idiopathic PD, is known to act as regulator of endophilin-A, which is a membrane protein that binds, localizes, and stabilizes synj1 at membranes during synaptic vesicle recycling and that has been shown to be associated with an increased risk for PD. Increased lrrk2 kinase activity has been shown to inhibit endophilin-A membrane association while decreased lrrk2 activity facilitates endophilin-A membrane association. Thus, lrrk2- and synj1-associated parkinsonism as well as idiopathic PD might be tied to defects in endophilin-A membrane association properties. Because synj1 also binds to dynamin-1, nucleotide variation of which causes epilepsy, the association of synj1 genetic variability with epileptic syndromes might be explained by impairments in the binding of synj1 to dynamin-1 that might be caused by nonsense SYNJ1 mutations (those causing epileptic syndromes) but not by missense mutations (those causing parkinsonism). The identification of Dnajb2 mutations in a family with spinal muscular atrophy (SMA) and parkinsonism by my team is another great example. DNAJB2 mutations were previously known to cause SMA but never associated with parkinsonism. Given the fact that dnajb2 binds to both tau and hsp70, which solubilize alpha-synuclein and promote the degradation of its insoluble forms via proteasome or chaperone-mediated autophagy, it is not surprising that defects in DNAJB2 are also associated with parkinsonism, as they might impair its binding with both tau and hsp70, resulting in alpha-synuclein aggregation and parkinsonism. Therefore, my laboratory models these complex genes in the zebrafish system in order to gain a deep understanding of the biological processes associated with the diverse clinical manifestations observed in these complex forms of parkinsonism.
Taken together, my laboratory focuses on the identification and characterization of genetic determinants underlying both simple and complex forms of parkinsonism to elucidate all genomic factors contributing to disease pathogenesis and to obtain a deep knowledge of the biology of each of the implicated targets in order to translate those discoveries into potential targets for drug discovery and development.
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Coro Paisán-Ruiz, PhD, is an Associate Professor of Neurology, Psychiatry and Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai (New York). She is currently on the Program Committee of the 6th World Parkinson Coalition.
Ideas and opinions expressed in this post reflect that of the author solely. They do not reflect the opinions or positions of the World Parkinson Coalition®