Current Research

The long-term goal of the McLoughlin Lab is to understand the pathogenic mechanisms underlying hereditary ataxias. By uncovering these mechanisms, we aim to facilitate the development of biomarkers and disease-modifying therapies that target the most promising molecular and cellular pathways. Our research primarily focuses on Spinocerebellar Ataxia Type 3 (SCA3), the most common dominantly inherited form of ataxia. These efforts are crucial for addressing these devastating, often fatal disorders, which currently lack effective treatments.

UNDERSTANDING SCA3 PATHOGENESIS:

Due to the selective degeneration of neuronal populations, early research in polyQ disorders has taken a neuron-centric point of view. It is important to note, however, that glial cells, once only considered secondary supporting cells, are now recognized as vital components of the CNS that contribute greatly to neuronal health and contributors to neurodegenerative disease. From our longitudinal RNAseq SCA3 mouse studies, we identified oligodendrocyte myelination and sterol biosynthesis to be major pathways or cellular processes dysregulated at early brainstem stages in our SCA3 mouse model that are rescued by ASO therapy. In the past few years (funded by an R01 NS122751; 2021-2026), my lab has defined how widespread oligodendrocyte dysfunction is in SCA3 using a variety of cell, mouse models, and human tissue samples using biochemical and histological analyses1-6. Two current research directions under this focus are 1) the development of novel SCA3 conditional mouse models to determine the extent that mutant ATXN3 expression elicits oligodendrocyte dysfunction and contributions to disease phenotypes and 2) investigations into the molecular mechanisms underlying oligodendrocyte dysfunction in SCA3 using aforementioned models and techniques. By defining oligodendrocytes’ role in SCA3 disease, my lab will answer whether this vulnerable cell type needs to be a target of emerging SCA3 therapies.

McLoughlin, H. S. et al. ASO silencing reverses abnormal neurochemistry in spinocerebellar ataxia 3 mice. Ann Neurol 94, doi:10.1002/ana.26713 (2023).
Putka, A. F., Mato, J. P. & McLoughlin, H. S. Myelinating Glia: Potential Therapeutic Targets in Polyglutamine Spinocerebellar Ataxias. Cells 12, doi:10.3390/cells12040601 (2023).
Schuster, K. H. et al. Disease-associated oligodendrocyte signatures are spatiotemporally dysregulated in spinocerebellar ataxia type 3. Front Neurosci 17, 1118429, doi:10.3389/fnins.2023.1118429 (2023).
Schuster, K. H., Putka, A. F. & McLoughlin, H. S. Pathogenetic Mechanisms Underlying Spinocerebellar Ataxia Type 3 Are Altered in Primary Oligodendrocyte Culture. Cells 11, doi:10.3390/cells11162615 (2022).
Schuster, K. H. et al. ASOs are an effective treatment for disease-associated oligodendrocyte signatures in premanifest and symptomatic SCA3 mice. Molecular Therapy 32, doi:10.1016/j.ymthe.2024.02.033 (2024).
Schuster, K. H. et al. Impaired oligodendrocyte maturation is an early feature in SCA3 disease pathogenesis. Journal of Neuroscience 42, doi:10.1523/Jneurosci.1954-20.2021 (2022).

ADVANCING BIOMARKER DEVELOPMENT:

Several treatment strategies for ataxias inspired by basic science laboratories, including my own, are ripe for testing in the clinic. Unfortunately, we do not have sensitive or specific biomarkers for i) predicting disease course in SCAs, ii) monitoring disease severity/outcome, iii) tracking response in clinical trials, or iv) improving the timing of therapeutic interventions7. We previously collaborated with Dr. Gülin Öz through a funded NIH R21 (NS111154; 2019-2022) to develop MRS biomarkers that are correlated with SCA3 disease progression and with ASO-mediated reversal of pathology and behavior in mice8-9. My lab conducted multiplexed protein studies with banked SCA3 plasma samples and found numerous novel proteins that can differentiate between symptomatic SCA3 patients and healthy individuals. In our data, we confirmed changes in neurofilament light (NfL), which currently serves as the benchmark plasma biomarker for predicting the onset and progression of SCA3 disease. Additionally, we’ve begun validating these biomarkers in our SCA3 mouse models for preclinical development10. We are currently assessing/modeling plasma biomarkers for tracking disease progression and treatment response. We believe this work can help identify biomarkers that can enable trials to be powered with smaller sample sizes and provide objective measures for determining disease onset, progression, and therapeutic response more precisely.

Santorelli, F. M. et al. Standards of Fluid Biomarker Collection and Pre-analytical Processes in Humans and Mice: Recommendations by the Ataxia Global Initiative Working Group on Biomarkers. Cerebellum, doi:10.1007/s12311-023-01561-1 (2023).
McLoughlin, H. S. et al. ASO silencing reverses abnormal neurochemistry in spinocerebellar ataxia 3 mice. Ann Neurol, doi:10.1002/ana.26713 (2023).
Costa, M. D. C. et al. In Vivo Molecular Signatures of Cerebellar Pathology in Spinocerebellar Ataxia Type 3. Mov Disord, doi:10.1002/mds.28140 (2020).
Mengel, D. et al. Blood neurofilament light chain levels are associated with disease progression in a transgenic SCA3 mouse model. Disease Models and Mechanisms. doi:10.1242/dmm.050144 (2023).

DEVELOPING THERAPIES FOR SCA3:

Since expression of the mutant ATXN3 protein is an early and necessary step in SCA3 disease pathogenesis, strategies to reduce expression of the disease gene or enhance clearance itself are high on the list of potential therapies. The lab is pursuing preclinical research programs targeting ATXN3 using antisense oligonucleotide and viral-mediate RNAi approaches11-12. Additionally, we have therapeutic studies arising from our mechanistic programs in the lab.

Moore, L. R. et al. Evaluation of Antisense Oligonucleotides Targeting ATXN3 in SCA3 Mouse Models. Molecular Therapy Nucleic Acids 7, 200-210, doi:10.1016/j.omtn.2017.04.005 (2017).
McLoughlin, H. S. et al. Oligonucleotide therapy mitigates disease in Spinocerebellar Ataxia Type 3 mice. Annals of Neurology 81, 64-77, doi:10.1002/ana.25264 (2018).

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