We utilize multi-omic approaches to study
neurodegenerative diseases
Polyglutamine
Diseases
Spinocerebellar Ataxia Type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by an increased number of unstable CAG repeats in the human ATXN1 gene. Spinal & Bulbar Muscular Atrophy (SBMA) is an X-linked progressive neuromuscular disease caused by expansion of polymorphic CAG repeats in the Androgen Receptor (AR) gene. Huntington’s Disease (HD) is another dominantly inherited neurodegenerative disease caused by a CAG repeat in the human Huntingtin (Htt) gene.
Alzheimer’s Disease &
Related Dementias (ADRDs)
Alzheimer’s Disease (AD) is an age-related neurodegenerative disease characterized by progressive memory loss and the accumulation of extracellular amyloid beta into plaques, and hyperphosphorlyated tau into intraneuronal neurofibrillary tangles. TDP-43 Proteinopathies are characterized by an aberrant accumulation of cytoplasmic TDP-43 and includes a majority of Amyotrophic Lateral Sclerosis (ALS) and a subset of Frontotemporal Dementia (FTD) cases.
Regional Vulnerability
While ataxin-1 is expressed widely throughout the brain, spinal cord, as well as peripheral tissues including skeletal muscle, research on SCA1 has historically focused heavily on cerebellar and brainstem degeneration. The impact of mutant ataxin-1 outside of these regions remains relatively unexplored in SCA1. Therefore, gaining a better understanding of the pathogenic mechanisms of polyQ-expanded ataxin-1 across other brain regions and peripheral tissues involved in SCA1 will be crucial for identifying pharmacological targets and developing effective therapeutic interventions.In addition to the cerebellum, our lab is also interested in the cortex in the context of SCA1 where we have demonstrated novel disease pathology.
Read More:
Luttik K, Olmos V, Owens A, et al. Identifying Disease Signatures in the Spinocerebellar Ataxia Type 1 Mouse Cortex. Cells. 2022;11(17):2632. Published 2022 Aug 24. doi:10.3390/cells11172632
Olmos V, Gogia N, Luttik K, Haidery F, Lim J. The extra-cerebellar effects of spinocerebellar ataxia type 1 (SCA1): looking beyond the cerebellum. Cell Mol Life Sci. 2022;79(8):404. Published 2022 Jul 8. doi:10.1007/s00018-022-04419-7
Protein Quality Control
Alzheimer’s disease and related tauopathies comprise a group of neurodegenerative diseases characterized by the presence of hyperphosphorylated tau that aggregates to form insoluble neurofibrillary tangles (NFTs), leading to impairments in cell signaling pathways, synapse loss, and eventually cell death. Mechanisms to activate protein quality control machinery such as the autophagy-lysosome pathway could aid in the clearance of these toxic tau species and potentially rescue tau-associated pathology. Our lab recently identified Nemo-like kinase (NLK) as a negative regulator of lysosome biogenesis. Current studies in the lab are working to elucidate other components of this molecular pathway.
Read More:
Tejwani L, Jung Y, Kokubu H, et al. Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43-related neurodegeneration. J Clin Invest. 2023;133(16):e138207. Published 2023 Aug 15. doi:10.1172/JCI138207
Dong T, Tejwani L, Jung Y, et al. Microglia regulate brain progranulin levels through the endocytosis/lysosomal pathway. JCI Insight. 2021;6(22):e136147. Published 2021 Nov 22. doi:10.1172/jci.insight.136147
Neuron–Glia Interactions
Modern neuroscience primarily focuses on neurons and largely neglects glial brain cell types such
as oligodendroglia, astrocytes, and microglia.
Our lab has recently shown that astrocytes, the most abundant glial population in the brain, become reactive before Purkinje cell (PC) loss occurs in the SCA1 knock-in mouse model. Using conditional mouse genetics, single-cell omics, behavioral and histopathological analysis, we seek to understand whether these previously reported astrocytic changes are in response to PC neuronal dysfunction, or, instead, causally contribute to neuronal pathology
Oligodendroglia, a term encompassing oligodendrocyte precursor cells (OPCs) to mature differentiated oligodendrocytes (OLs), serve a critical role in proper neuronal health and function by providing myelination along the axon and facilitating metabolic support and neurotransmission. Currently, OL dysfunction has been identified in numerous diseases including Alzheimer’s Disease and Spinocerebellar Ataxias. Furthermore, we have demonstrated that differentiation from OPCs to OLs is impaired in SCA1 patients and mice and that OL dysfunction precedes neuronal impairments. To further characterize disease progression, we have created a conditional knock-in SCA1 model in oligodendroglia lineage cells.
Read More:
Tejwani L, Ravindra NG, Lee C, et al. Longitudinal single-cell transcriptional dynamics throughout neurodegeneration in SCA1. Neuron. 2024;112(3):362-383.e15. doi:10.1016/j.neuron.2023.10.039
Luttik K, Tejwani L, Ju H, et al. Differential effects of Wnt-β-catenin signaling in Purkinje cells and Bergmann glia in spinocerebellar ataxia type 1. Proc Natl Acad Sci U S A. 2022;119(34):e2208513119. doi:10.1073/pnas.2208513119