About

Marija Cvetanovic, PhD, is an Associate Professor in the Department of Neuroscience at the University of Minnesota Medical School. Her research focuses on understanding how different brain cells and their interactions influence the onset and progression of neurodegenerative diseases. Specifically, she studies the involvement of astrocytes and microglia in the pathogenesis of inherited neurodegenerative diseases such as Spinocerebellar ataxia type 1 (SCA1), which is part of the family of polyglutamine diseases including Huntington's disease. Her laboratory employs mouse genetics, cell and molecular biology techniques, mouse behavior analysis, confocal microscopy, and flow cytometry to increase knowledge of the cellular and molecular pathways underlying neurodegenerative disorders and to explore new therapeutic avenues.

Research topics

• Medicine
• Biology
• Neuroscience
• Immunology
• Pathology
• Cell biology
• Bioinformatics
• Internal medicine
• Psychology
• Genetics

Selected publications

• Mutant ATXN1 impacts human and mouse microglia and contributes to cognitive, mood, and motor deficits in SCA1 mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-12

  articleOpen accessSenior authorCorresponding

  Microglia, resident immune cells of the brain, are important players in neurodegeneration. While microglial activation is a hallmark of many neurodegenerative diseases, the specific role of microglia intrinsic factors in microglial activation and disease pathogenesis remains unknown. Spinocerebellar ataxia type-1 (SCA1) is an inherited autosomal dominant neurodegenerative disease characterized by severe neuronal loss and early microglial activation in the cerebellum. SCA1 is caused by CAG repeat expansion in the ubiquitously expressed ATAXIN1 (ATXN1) gene. Using human microglia differentiated from SCA1 patient derived iPSCs, we found that mutant ATXN1 is sufficient to alter morphology, gene and protein expression in human microglia in a cell-autonomous manner. Moreover, compared to controls, human SCA1 microglia exhibited increased phagocytosis and pro-inflammatory cytokine production, indicating an immune priming. To determine the extent to which mutant ATXN1 in microglia contributes to SCA1 pathogenesis and behavioral symptoms, we removed mutant ATXN1 from microglia and macrophages in a novel conditional SCA1 mouse model, f-ATXN1146Q/2Q mice. Microglial mutant ATXN1 reduction led to a marked correction in microglia phenotype, in particular in the transcriptomic signature of interferon type 1 mediated immune response, reduced microglial density and resulted in smaller microglia with reduced branching in the cerebellum. Pathology of Purkinje neurons and cerebellar astrogliosis were also ameliorated. Utilizing a battery of behavioral tests, we found that microglia and macrophage mutant ATXN1 reduction ameliorated cognitive, mood, and motor deficits in SCA1 mice. Together, these results indicate that mutant ATXN1 directly impacts microglial phenotype in SCA1, contributing to SCA1 pathology and behavioral deficits.

  PublisherOA PDFDOI

• Neural basis for mutant ATAXIN-1 induced respiratory dysfunction in mouse models of spinocerebellar ataxia type 1

  Neurobiology of Disease · 2026-03-17

  articleOpen accessSenior authorCorresponding

  Spinocerebellar ataxia type 1 is a neurodegenerative disease characterized by motor dysfunction and premature death usually from compromised swallowing and respiration. Using plethysmography, we characterized respiration in the conditional f-ATXN1 146Q/2Q SCA1 model. We found a progressive elevation of baseline respiration that impairs ability of f-ATXN1 146Q/2Q mice to increase breathing during challenge. To delineate regions contributing to respiratory dysfunction, f-ATXN1 146Q/2Q mice were crossed with Nestin-Cre and Acta1-Cre mice, respectively. Respiration improved by removing mATXN1 from neural lineages, but not from skeletal muscle demonstrating mATXN1 in the central nervous system is a key driver of respiratory dysfunction in SCA1 mouse models. Moreover, respiratory dysfunction in SCA1 mice involves two aspects: behavioral dysregulation exhibited as increased movement during plethysmography, and functional dysregulation of respiratory circuitry. As both of these aspects are rescued by deleting mATXN1 from neural cells, we further investigated the role of cerebellar Purkinje cells and chemosensing neurons in the brain stem in SCA1 respiratory phenotype. Our results indicate complex multiregional etiology of respiratory dysfunction. Mechanistically we found that in contrast to most other SCA1 symptoms, nuclear localization of mATXN1 does not play a key role in respiratory dysfunction. • SCA1 mice exhibit progressive elevation of baseline respiration that impairs their ability to increase breathing during respiratory challenge. • Respiratory dysfunction in SCA1 mice involves two aspects: behavioral dysregulation exhibited as increased movement during plethysmography, and functional dysregulation of respiratory circuitry. • Respiration improved by removing mATXN1 from neural lineages, but not from skeletal muscle demonstrating mATXN1 in the central nervous system is a key driver of respiratory dysfunction in SCA1 mouse models. In contrast to most other SCA1 symptoms, nuclear localization of mATXN1 fail to improve respiratory dysfunction.

  PublisherDOI

• CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington's disease

  Zenodo (CERN European Organization for Nuclear Research) · 2026-02-19

  articleOpen access

  Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in theHTT gene for which no therapies are available. HTT mutation causes protein misfolding and aggregation, preferentiallyaffecting medium spiny neurons (MSNs) of the basal ganglia. Transcriptional perturbations in synaptic genesand neuroinflammation are key processes that precede MSN dysfunction and motor symptom onset. Understandingthe interplay between these processes is crucial to develop effective therapeutic strategies to treat HD. We investigatedthe role of protein kinase CK2α’, a kinase upregulated in MSNs in HD and previously associated with Parkinson’sdisease (PD), in the regulation of neuroinflammation and synaptic function in HD. We used the heterozygous knock-inzQ175 HD mouse model and compared that to zQ175 mice lacking one allele of CK2α’ (zQ175:CK2α’(±)). CK2α’ haploinsufficiencyin zQ175 mice resulted in decreased levels of pro-inflammatory cytokines, HTT aggregation, astrogliosisand transcriptional alterations of synaptic genes related to glutamatergic signaling. zQ175:CK2α’(±) mice also presentedincreased frequency of striatal miniature excitatory postsynaptic currents (mEPSCs), an indicator of synapticactivity, and improved motor coordination compared to zQ175 mice. Neuropathological and phenotypic changesmediated by CK2α’ were connected to alpha-synuclein (α-syn) dysregulation and correlated with differences in α-synserine 129 phosphorylation (pS129-α-syn), a post-translational modification involved in α-synucleinopathy and shownto be regulated by CK2 in PD. pS129-α-syn was increased in the nuclei of MSNs in zQ175 mice and in the striatumof patients with HD, and it decreased in zQ175:CK2α’(±) mice. Collectively, our data established a novel connectionbetween CK2α’, neuroinflammation and synaptic gene dysregulation with synucleinopathy in HD and suggestedcommon molecular mechanisms of neurodegeneration between HD and PD. Our results also support CK2α’ inhibitionas a potential therapeutic strategy to modulate neuronal function and neuroprotection in HD.

  PublisherDOI

• Experimental Therapeutic Approaches: Molecular, Genetic, and Behavioral

  Contemporary clinical neuroscience · 2026-01-01

  book-chapterSenior authorCorresponding
  PublisherDOI

• CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington's disease

  Zenodo (CERN European Organization for Nuclear Research) · 2026-02-19

  articleOpen access

  Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in theHTT gene for which no therapies are available. HTT mutation causes protein misfolding and aggregation, preferentiallyaffecting medium spiny neurons (MSNs) of the basal ganglia. Transcriptional perturbations in synaptic genesand neuroinflammation are key processes that precede MSN dysfunction and motor symptom onset. Understandingthe interplay between these processes is crucial to develop effective therapeutic strategies to treat HD. We investigatedthe role of protein kinase CK2α’, a kinase upregulated in MSNs in HD and previously associated with Parkinson’sdisease (PD), in the regulation of neuroinflammation and synaptic function in HD. We used the heterozygous knock-inzQ175 HD mouse model and compared that to zQ175 mice lacking one allele of CK2α’ (zQ175:CK2α’(±)). CK2α’ haploinsufficiencyin zQ175 mice resulted in decreased levels of pro-inflammatory cytokines, HTT aggregation, astrogliosisand transcriptional alterations of synaptic genes related to glutamatergic signaling. zQ175:CK2α’(±) mice also presentedincreased frequency of striatal miniature excitatory postsynaptic currents (mEPSCs), an indicator of synapticactivity, and improved motor coordination compared to zQ175 mice. Neuropathological and phenotypic changesmediated by CK2α’ were connected to alpha-synuclein (α-syn) dysregulation and correlated with differences in α-synserine 129 phosphorylation (pS129-α-syn), a post-translational modification involved in α-synucleinopathy and shownto be regulated by CK2 in PD. pS129-α-syn was increased in the nuclei of MSNs in zQ175 mice and in the striatumof patients with HD, and it decreased in zQ175:CK2α’(±) mice. Collectively, our data established a novel connectionbetween CK2α’, neuroinflammation and synaptic gene dysregulation with synucleinopathy in HD and suggestedcommon molecular mechanisms of neurodegeneration between HD and PD. Our results also support CK2α’ inhibitionas a potential therapeutic strategy to modulate neuronal function and neuroprotection in HD.

  PublisherDOI

• Sex Differences in a Novel Mouse Model of Spinocerebellar Ataxia Type 1 (SCA1)

  International Journal of Molecular Sciences · 2025-03-14 · 4 citations

  articleOpen accessSenior authorCorresponding

  Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant inherited neurodegenerative disease caused by the expansion of glutamine (Q)-encoding CAG repeats in the gene ATAXIN1 (ATXN1). Patients with SCA1 suffer from movement and cognitive deficits and severe cerebellar pathology. Previous studies identified sex differences in disease progression in SCA1 patients, but whether these differences are present in mouse models is unclear. Using a battery of behavioral tests, immunohistochemistry of brain slices, and RNA sequencing, we examined sex differences in motor and cognitive performance, cerebellar pathology, and cerebellar gene expression changes in a recently created conditional knock-in mouse model f-ATXN1146Q expressing human coding regions of ATXN1 with 146 CAG repeats. We found worse motor performance and weight loss accompanied by increased microglial activation and an increase in immune viral response pathways in male f-ATXN1146Q mice.

  PublisherOA PDFDOI

• An expanded polyglutamine in ATAXIN1 results in a loss-of-function that exacerbates severity of Multiple Sclerosis in an EAE mouse model

  Research Square · 2025-04-14

  preprintOpen access
  PublisherOA PDFDOI

• A Mouse Model of Neurotoxicity Induced by Human CD19-Specific CAR T-cells: CAR T-cells Accumulate in the Subarachnoid Space Prior to Trafficking into the Brain Parenchyma 3807

  The Journal of Immunology · 2025-11-01

  articleOpen access

  Abstract Description Immune cell-associated neurotoxicity syndrome (ICANS) is a common morbidity associated with human CD19-specific chimeric antigen receptor T-cell (CAR19) immunotherapy. The etiology of ICANS is not well understood but is thought to involve breakdown of the blood-brain barrier (BBB) and subsequent entry of proinflammatory cytokines and CAR19 cells into the brain parenchyma. To understand how CAR19 therapy leads to ICANS, we developed a human CD19 transgenic (hCD19Tg) mouse model that replicates the anti-tumor efficacy and all reported toxicities – including ICANS - associated with CAR19 clinical therapy. Although the BBB is compromised in our model, it does not appear to be the major entry site of CAR19 cells. Rather, two-photon microscopy reveals that CAR19 cells first accumulate in the subarachnoid space and then migrate down into the parenchyma through perivascular spaces. Co-injected control CAR T-cells also accumulate in the subarachnoid space but do not migrate into the parenchyma, suggesting trafficking is antigen-specific. We are testing the hypotheses that: 1) accumulation of CAR19 cells in the subarachnoid space reflects their localization to the subarachnoid lymphatic-like membrane (SLYM) and 2) their subsequent migration into the parenchyma through the perivasculature is driven via recognition of hCD19 on mural cells. By understanding how CAR19 cells enter the brain, we hope to develop strategies to blunt or prevent ICANS. Funding Sources Supported by NIH/NCI R01 CA263090 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

  PublisherOA PDFDOI

• An expanded polyglutamine in ATAXIN1 results in a loss-of-function that exacerbates severity of Multiple Sclerosis in an EAE mouse model

  Journal of Neuroinflammation · 2025-04-30 · 2 citations

  articleOpen access

  Ataxin-1 (ATXN1) is a protein in which expansion of its polyglutamine tract causes the neurodegenerative disorder spinocerebellar ataxia type 1 (SCA1) via a gain-of-function. Wild type ATXN1 was recently shown to have a protective role in regulating severity of experimental autoimmune encephalomyelitis (EAE), a well-established mouse model for Multiple sclerosis (MS). This study further investigates the role of ATXN1 with an expanded polyglutamine tract in the context of MS using an EAE mouse model. Hemizygous Atxn1 (Atxn12Q/−) mice or f-ATXN1146Q/2Q, heterozygous mice that have one copy of the endogenous mouse gene replaced with a polyQ expanded pathogenic human ATXN1 gene, were injected with myelin oligodendrocytes glycoprotein (MOG35 − 55) peptide to induce EAE. Immunohistochemical and biochemical approaches were used to analyze the degree of demyelination, cell loss, axonal degeneration as well as detecting the activated immune cells and inflammatory cytokines upon EAE induction in Atxn12Q/− and f-ATXN1146Q/2Q mice. Our findings reveal that a loss-of-function of wild type Atxn1 in Atxn12Q/− and f-ATXN1146Q/2Q mice significantly exacerbates the EAE symptoms, leading to increased demyelination, oligodendrocytes loss, heightened axon degeneration, and greater clinical disability in affected mice. Importantly, the data reveals that neurotoxic astrocytes are activated at acute stage of disease (PID-14) and at the chronic stage of disease (PID-30) neurotoxic astrocytes no longer show signs of activation. The data also demonstrated enhanced infiltration of immune cells into the lesions of mutant mice. These results indicate that ATXN1 plays a protective role in modulating immune responses and maintaining neural integrity during MS. Importantly, expansion of the polyQ tract in ATXN1 results in a loss-of-function in ATXN1’s ability to dampen the immune response. Understanding the functional role of ATXN1 in MS pathogenesis may open new avenues for therapeutic strategies aimed at mitigating disease progression.

  PublisherOA PDFDOI

• 1050 Neurotoxicity induced by human CD19-specific CAR T-cells in a mouse model: CAR T-cells enter the brain parenchyma from the subarachnoid space and increase spontaneous neuronal signaling

  Regular and Young Investigator Award Abstracts · 2025-11-01

  articleOpen access
  PublisherOA PDFDOI

Recent grants

• Etiology of cognitive decline in Spinocerebellar ataxia type 1

  NIH · $1.8M · 2020–2025

• Understanding cellular and molecular mechanisms of neurodegeneration

  NIH · $1.3M · 2018–2022

Frequent coauthors

• Ying Zhang

  91 shared

• David S. Ucker

  University of Illinois Urbana-Champaign

  38 shared

• Jerrold S. Levine

  New York Medical College

  20 shared

• Alyssa Soles

  University of Minnesota

  17 shared

• Vimal Patel

  14 shared

• Huda Y. Zoghbi

  Baylor College of Medicine

  14 shared

• Justin E. Mitchell

  Illinois College

  13 shared

• Carrie Sheeler

  University of Minnesota

  13 shared