Neurodegenerative diseases affect millions of people worldwide, and health care costs related to treating these illnesses have skyrocketed. They include Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, polyglutamine diseases, and hereditary ataxias, etc.The main research goal of my laboratory is to better understand the molecular and cellular mechanisms that are responsible for neurodegeneration and ultimately to translate our findings into the development of therapeutics for neurodegenerative diseases. To achieve this goal, we focus on polyglutamine diseases as model systems. Polyglutamine diseases are dominantly inherited neurodegenerative conditions caused by an expansion of a CAG trinucleotide repeat encoding a glutamine tract in the respective disease-causing proteins. Polyglutamine expansion makes the host protein toxic, resulting in the formation of mutant protein aggregates and cell death. The commonalities in the nature of these mutations and the presentation of the different polyglutamine disorders suggest the occurrence of a common pathogenic mechanism. Such mechanism, however, has remained elusive and to date there are no cures or even effective therapies for most of these diseases. We have been focusing on two distinct polyglutamine diseases, named spinocerebellar ataxia type 1 (SCA1) and spinal and bulbar muscular atrophy (SBMA). SCA1 is a dominantly inherited disease characterized by the progressive degeneration of neurons, specifically those in the cerebellum and brainstem. SBMA is an X-linked progressive neuromuscular disease. SBMA patients present with progressive weakness and muscle atrophy resulting from the degeneration of the motor neurons and skeletal muscles.
Extensive Research Description
We have recently identified Nemo-Like Kinase (NLK) as a genetic modifier in the pathogenesis of SCA1 and SBMA and thus as a novel putative therapeutic target for those diseases. By utilizing a variety of experimental approaches, including biochemistry, cell biology, and Drosophila and mouse genetics, we showed that reducing NLK expression lowers the severity of protein toxicity in SCA1 and SBMA. The finding that NLK and its signaling pathway affect the activity of two distinct polyglutamine diseases provide evidence for the occurrence of common pathogenetic mechanisms in this group of neurodegenerative diseases.
Our studies have had an important impact on the understanding of mechanistic aspects of polyglutamine expansion-dependent diseases. However, many questions remain open, such as, for example, how expression of mutant proteins results in cell type-specific neuronal dysfunction and loss. To address these questions, we utilize the combined use of biochemistry, cell biology and molecular genetics with behavioral studies in vivo animal models. The lab is currently investigating several questions.
First, we continue to study how NLK signaling is responsible for modulating the neurodegenerative phenotypes of SCA1 and SBMA. The role of NLK in mutant proteins’ post-translational modifications and their clearance will be determined and their contribution to disease toxicity will be characterized.
Second, we study how the disease-causing mutant proteins produce toxic effects by impacting signaling pathways (e.g. Wnt signaling in SCA1) in vulnerable tissues in a cell type-specific manner.
Third, we are developing a novel SCA1 model using human pluripotent stem cells (e.g. SCA1 patient-derived induced pluripotent stem cells) and investigate the pathogenic mechanisms underlying SCA1 in a human SCA1 neuronal context. We will follow-up and expand these studies.
We believe that this research will not only fundamentally advance our understanding of the pathogenic mechanisms of neurodegenerative diseases, but also suggest new therapeutic strategies of the treatment to these devastating neurodegenerative diseases.
- Todd TW, Kokubu H, Miranda HC, Cortes CJ, La Spada AR, and Lim J. (2015). Nemo-like kinase is a novel regulator of spinal and bulbar muscular atrophy. eLife, 2015 Aug 26;4. doi: 10.7554/eLife.08493. [Epub ahead of print]
- Ju H, Kokubu H, Todd TW, Kahle JJ, Kim S, Richman R, Chirala K, Orr HT, Zoghbi HY, and Lim J. (2013). Polyglutamine disease toxicity is regulated by Nemo-like kinase in spinocerebellar ataxia type 1. Journal of Neuroscience 33, 9328-9336.
- Lim J, Crespo-Barreto J, Jafar-Nejad P, Bowman AB, Richman R, Hill DE, Orr HT, and Zoghbi HY. (2008). Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature 452, 713-718.
- Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual J-F, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási A-L, Vidal M, and Zoghbi HY. (2006). A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 125, 801-814.