Decreasing mutant ATXN1 nuclear localization improves a spectrum of SCA1-like phenotypes and brain region transcriptomic profiles

Handler, Hillary P.; Duvick, Lisa A.; Mitchell, Jason S.; Cvetanović, Marija; Reighard, Molly; Soles, Alyssa; Mather, Kathleen B; Rainwater, Orion; Serres, Shannah; Nichols-Meade, Tessa; Coffin, Stephanie L.; You, Yun; Ruis, Brian L.; O’Callaghan, Brennon; Henzler, Christine; Zoghbi, Huda Y.; Orr, Harry T.

doi:10.1016/j.neuron.2022.11.017

Cited by 16 publications

(10 citation statements)

References 50 publications

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“…Notably, deletion of f-ATXN1 146Q from muscle substantially reduced kyphosis that in mice is associated with paraspinal skeletal muscle atrophy 18 as well as restored normal dorsiflexor strength, muscle mass and fiber size. As seen for other SCA1-like phenotypes, motor dysfunction, cognitive deficits, and premature lethality 20 , proper nuclear localization of expanded ATXN1 was shown to be critical for muscle pathogenesis. These results show that f-ATXN1 146Q/2Q along with f-ATXN1 146Q/2Q ; Acta1-Cre will provide an excellent experimental platform for elucidating the molecular aspects of ATXN1[146Q]-induced muscle pathogenesis.…”

Section: Discussionmentioning

confidence: 77%

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Delineating regional vulnerability in the neurodegenerative disease SCA1 using a conditional mutant ATXN1 mouse

Duvick

Southern

Benzow

et al. 2023

Preprint

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Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an expanded polyglutamine tract in the widely expressed ATXN1 protein. To elucidate anatomical regions and cell types that underlie mutant ATXN1-induced disease phenotypes, we developed a floxed conditional knockout mouse model (f-ATXN1146Q/2Q) having mouse Atxn1 coding exons replaced by human exons encoding 146 glutamines. F- ATXN1146Q/2Q mice manifest SCA1-like phenotypes including motor and cognitive deficits, wasting, and decreased survival. CNS contributions to disease were revealed using ATXN1146Q/2Q;Nestin-Cre mice, that showed improved rotarod, open field and Barnes maze performances. Striatal contributions to motor deficits were examined using f- ATXN1146Q/2Q;Rgs9-Cre mice. Mice lacking striatal ATXN1146Q/2Q had improved rotarod performance late in disease. Muscle contributions to disease were revealed in f- ATXN1146Q/2Q;ACTA1-Cre mice which lacked muscle pathology and kyphosis seen in f- ATXN1146Q/2Q mice. Kyphosis was not improved in f-ATXN1146Q/2Q;Nestin-Cre mice. Thus, optimal SCA1 therapeutics will require targeting mutant ATXN1 toxic actions in multiple brain regions and muscle.

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Section: Discussionmentioning

confidence: 77%

“…Recently, we found that proper nuclear localization of mutant ATXN1 is critical for many disease-like phenotypes including motor dysfunction, cognitive deficits, and premature lethality 20 . Like f-ATXN1 146Q/2Q mice, we observed smaller dorsiflexor muscle mass (Fig.…”

Section: Resultsmentioning

confidence: 99%

Delineating regional vulnerability in the neurodegenerative disease SCA1 using a conditional mutant ATXN1 mouse

Duvick

Southern

Benzow

et al. 2023

Preprint

Self Cite

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“…Proper nuclear localization of mutant ATXN1 is critical for many disease-like phenotypes, including motor dysfunction, cognitive deficits, and premature lethality (25). Like in f-ATXN1 146Q/2Q mice, smaller dorsiflexor muscle mass and torque (Figure 7, A-C) and smaller fiber size (Figure 7F), indicating the presence of a skeletal muscle myopathy, are seen in Atxn1 175Q/2Q mice as early as 12 weeks of age.…”

Section: Resultsmentioning

confidence: 97%

Mapping SCA1 regional vulnerabilities reveals neural and skeletal muscle contributions to disease

Duvick,

Southern,

Benzow

et al. 2024

JCI Insight

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“…Furthermore, KPNB not only returns TDP-43 to the nucleus but can also suppress TDP-43-induced neurodegeneration (Khalil et al, 2022). However, in the case of ATXN1 (82Q), nuclear localization of the protein is linked to its toxic effects, since mutating the NLS in polyQ-expanded ATXN1 actually removes its pathogenicity in mice (Klement et al, 1998;Handler et al, 2023), therefore KPNA must be acting in a different way to suppress ATXN1 (82Q)-induced neurodegeneration. Other potential mechanisms of neuroprotection have been proposed for KPNs, including evidence supporting chaperoning and disaggregation functions (Guo et al, 2018;Pasha et al, 2021;Jäkel et al, 2002).…”

Section: Increased Kpna Levels Reduce Overall Nuclear Atxn1 (82q) Acc...mentioning

confidence: 99%

“…ATXN1 aggregates are pathogenic when they localize to the nucleus and form nuclear bodies (NBs) (Klement et al, 1998;Zhang, Hinde, et al, 2020). PolyQ-expanded ATXN1 without its functional nuclear localization signal does not cause disease phenotypes in SCA1 mouse models (Klement et al, 1998;Handler et al, 2023). This indicates that nuclear localization of mutant ATXN1 is required for pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Increased Karyopherin Alpha Levels Attenuate Mutant Ataxin-1-Induced Neurodegeneration

Ruff,

Timperman,

Amador

et al. 2023

Preprint

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Neurodegenerative diseases are characterized by the abnormal accumulation of disease-driving proteins. Emerging evidence suggests that nucleocytoplasmic transport (NCT) components play a critical role in neurodegeneration. This study investigates the impact of modulating Karyopherin alpha (KPNA) levels on neurodegeneration induced by mutant Ataxin-1 (ATXN1) using a Drosophila model of Spinocerebellar Ataxia Type 1 (SCA1). Our findings reveal that ATXN1 (82Q) interacts with KPNAs in the nucleus and cytoplasm of neurons. Increasing KPNA levels alleviates ATXN1 (82Q)-induced neurodegeneration and progressive neuronal dysfunction. Surprisingly, mechanistic analyses demonstrate that elevated KPNA levels retain mutant ATXN1 in the cytoplasm, reducing its nuclear accumulation in the Drosophila central nervous system. Moreover, elevated KPNA levels lead to a decrease in soluble oligomeric ATXN1. These results indicate that KPNAs may act as chaperones for mutant ATXN1, preventing its nuclear translocation and reducing its pathological effects. Importantly, they also constitute a proof of principle that retaining mutant ATXN1 in the cytoplasm represents an attractive and viable therapeutic option. Given the dysregulation of Karyopherins in many neurodegenerative diseases and their emerging role as chaperones, the results presented here may extend beyond SCA1 into other disorders like Alzheimer's or Parkinson's disease.

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Decreasing mutant ATXN1 nuclear localization improves a spectrum of SCA1-like phenotypes and brain region transcriptomic profiles

Cited by 16 publications

References 50 publications

Delineating regional vulnerability in the neurodegenerative disease SCA1 using a conditional mutant ATXN1 mouse

Delineating regional vulnerability in the neurodegenerative disease SCA1 using a conditional mutant ATXN1 mouse

Mapping SCA1 regional vulnerabilities reveals neural and skeletal muscle contributions to disease

Increased Karyopherin Alpha Levels Attenuate Mutant Ataxin-1-Induced Neurodegeneration

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