Publications by authors named "Stefan M Pulst"

120 Publications

Staufen1 in Human Neurodegeneration.

Ann Neurol 2021 Mar 21. Epub 2021 Mar 21.

Department of Neurology, University of Utah, Salt Lake City, UT.

Objective: Mutations in the ATXN2 gene (CAG expansions ≥32 repeats) can be a rare cause of Parkinson's disease and amyotrophic lateral sclerosis (ALS). We recently reported that the stress granule (SG) protein Staufen1 (STAU1) was overabundant in neurodegenerative disorder spinocerebellar ataxia type 2 (SCA2) patient cells, animal models, and ALS-TDP-43 fibroblasts, and provided a link between SG formation and autophagy. We aimed to test if STAU1 overabundance has a role in the pathogenesis of other neurodegenerative diseases.

Methods: With multiple neurodegenerative patient-derived cell models, animal models, and human postmortem ALS tissue, we evaluate STAU1 function using biochemical and immunohistological analyses.

Results: We demonstrate STAU1 overabundance and increased total and phosphorylated mammalian target of rapamycin (mTOR) in fibroblast cells from patients with ALS with mutations in TDP-43, patients with dementia with PSEN1 mutations, a patient with parkinsonism with MAPT mutation, Huntington's disease (HD) mutations, and SCA2 mutations. Increased STAU1 levels and mTOR activity were seen in human ALS spinal cord tissues as well as in animal models. Changes in STAU1 and mTOR protein levels were post-transcriptional. Exogenous expression of STAU1 in wildtype cells was sufficient to activate mTOR and downstream targets and form SGs. Targeting STAU1 by RNAi normalized mTOR, suggesting a potential role for therapy in diseases associated with STAU1 overabundance.

Interpretation: STAU1 overabundance in neurodegeneration is a common phenomenon associated with hyperactive mTOR. Targeting STAU1 with ASOs or miRNA viral vectors may represent a novel, efficacious therapy for neurodegenerative diseases characterized by overabundant STAU1. ANN NEUROL 2021.
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http://dx.doi.org/10.1002/ana.26069DOI Listing
March 2021

Computational investigation of the impact of deep brain stimulation contact size and shape on neural selectivity.

J Neural Eng 2021 Mar 15. Epub 2021 Mar 15.

Neurology, Univ Utah, 175 North Medical Drive East, Salt Lake City, Utah, 84132, UNITED STATES.

Understanding neural selectivity is essential for optimizing medical applications of deep brain stimulation (DBS). We previously showed that modulation of the DBS waveform can induce changes in orientation-based selectivity, and that lengthening of DBS pulses or directional segmentation can reduce preferential selectivity for large axons. In this work, we sought to investigate a simple, but important question from a generalized perspective: how do the size and shape of the contact influence neural selectivity?We created multicompartment neuron models for several axon diameters and used finite element modeling with standard-sized cylindrical leads to determine the effects on changing contact size and shape on axon activation profiles and volumes of tissue activated. Contacts ranged in size from 0.04 to 16 mm2, compared with a standard size of 6 mm2.We found that changes in contact size are predicted to induce substantial changes in orientation-based selectivity in the context of a cylindrical lead, and changes in contact width or height can alter this selectivity. Smaller contact sizes were more effective in constraining neural activation to small, nearby axons. However, micro-scale contacts enable only limited spread of neural activation before exceeding standard charge density limitations; further, energetic efficiency is optimized by somewhat larger contacts.Small-scale contacts may be optimal for constraining stimulation in nearby grey matter and avoiding orientation-selective activation. However, given charge density limitations and energy inefficiency of micro-scale contacts, we predict that contacts sized similarly to or slightly smaller than segmented clinical leads may optimize energy efficiency while avoiding charge density limitations.
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http://dx.doi.org/10.1088/1741-2552/abeeaaDOI Listing
March 2021

The Helix: Editorial Changes.

Authors:
Stefan M Pulst

Neurol Genet 2020 Dec 3;6(6):e518. Epub 2020 Dec 3.

Department of Neurology University of Utah, Salt Lake City.

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http://dx.doi.org/10.1212/NXG.0000000000000518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803341PMC
December 2020

Splicing Control of Pontocerebellar Development.

Neuron 2021 01;109(2):191-192

Department of Neurology, University of Utah, 175 North Medical Drive East, 5th Floor, Salt Lake City, UT 84132, USA. Electronic address:

In this issue of Neuron, Chai et al. (2021) analyze several families with neurodegeneration and marked pontocerebellar hypoplasia and microcephaly and identify recessive (bi-allelic) mutations in peptidyl-prolyl isomerase-like 1 (PPIL1) and pre-RNA-processing-17 (PPR17). PPIL1 patient mutation knockin mice develop neuronal apoptosis. Loss of either protein affects splicing predominantly involving GC-rich and short introns.
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http://dx.doi.org/10.1016/j.neuron.2020.12.021DOI Listing
January 2021

Correction: Staufen 1 amplifies proapoptotic activation of the unfolded protein response.

Cell Death Differ 2021 Jan 19. Epub 2021 Jan 19.

Department of Neurology, University of Utah, 175 North Medical Drive East, 5th Floor, Salt Lake City, UT, 84132, USA.

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http://dx.doi.org/10.1038/s41418-021-00734-xDOI Listing
January 2021

Experiences with offering pro bono medical genetics services in the West Indies: Benefits to patients, physicians, and the community.

Am J Med Genet C Semin Med Genet 2020 12 4;184(4):1030-1041. Epub 2020 Dec 4.

Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

We describe our experiences with organizing pro bono medical genetics and neurology outreach programs on several different resource-limited islands in the West Indies. Due to geographic isolation, small population sizes, and socioeconomic disparities, most Caribbean islands lack medical services for managing, diagnosing, and counseling individuals with genetic disorders. From 2015 to 2019, we organized 2-3 clinics per year on various islands in the Caribbean. We also organized a week-long clinic to provide evaluations for children suspected of having autism spectrum disorder. Consultations for over 100 different individuals with suspected genetic disorders were performed in clinics or during home visits following referral by locally registered physicians. When possible, follow-up visits were attempted. When available and appropriate, clinical samples were shipped to collaborating laboratories for molecular analysis. Laboratory tests included karyotyping, cytogenomic microarray analysis, exome sequencing, triplet repeat expansion testing, blood amino acid level determination, biochemical assaying, and metabolomic profiling. We believe that significant contributions to healthcare by genetics professionals can be made even if availability is limited. Visiting geneticists may help by providing continuing medical education seminars. Clinical teaching rounds help to inform local physicians regarding the management of genetic disorders with the aim of generating awareness of genetic conditions. Even when only periodically available, a visiting geneticist may benefit affected individuals, their families, their local physicians, and the community at large.
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http://dx.doi.org/10.1002/ajmg.c.31871DOI Listing
December 2020

Detecting and Quantifying Ataxia-Related Motor Impairments in Rodents Using Markerless Motion Tracking With Deep Neural Networks.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:3642-3648

In this study we evaluate the application of video-based markerless motion tracking based on deep neural networks for the analysis of ataxia-specific movement abnormalities in rodent models of cerebellar ataxia. Based on a small amount (<100) of manually labeled video frames, markerless motion tracking enabled the extraction of movement trajectories and parameters characterizing ataxia-specific movement abnormalities. In the first experiment, we analyzed videos of 6 shaker and 4 wildtype rats and were able to reproduce thê5 Hz tremor frequency in the shaker rat without the usage of a force plate. In the second experiment, we investigated a spinocerebellar ataxia type 3 (SCA3) mouse model (6 mice aged 3 months and 3 mice aged 9 months) in a beam-balancing task. By establishing a parameter for the assessment of rhythmicity of gait (RoG), we not only found a significantly higher RoG in wildtype mice compared to affected SCA3 mice aged 9 months, but were also able to reveal a significantly lower than typical RoG in SCA3 mice aged 3 months which exhibit no abnormalities in visual inspection. These prototypical results suggest the capability of the presented methods for the application in upcoming therapeutic intervention trials to identify subtle changes in movement behavior.
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http://dx.doi.org/10.1109/EMBC44109.2020.9176701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092116PMC
July 2020

Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in spinocerebellar ataxia type 1.

Hum Mol Genet 2020 Nov;29(19):3249-3265

Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Selective neuronal vulnerability in neurodegenerative disease is poorly understood. Using the ATXN1[82Q] model of spinocerebellar ataxia type 1 (SCA1), we explored the hypothesis that regional differences in Purkinje neuron degeneration could provide novel insights into selective vulnerability. ATXN1[82Q] Purkinje neurons from the anterior cerebellum were found to degenerate earlier than those from the nodular zone, and this early degeneration was associated with selective dysregulation of ion channel transcripts and altered Purkinje neuron spiking. Efforts to understand the basis for selective dysregulation of channel transcripts revealed modestly increased expression of the ATXN1 co-repressor Capicua (Cic) in anterior cerebellar Purkinje neurons. Importantly, disrupting the association between ATXN1 and Cic rescued the levels of these ion channel transcripts, and lentiviral overexpression of Cic in the nodular zone accelerated both aberrant Purkinje neuron spiking and neurodegeneration. These findings reinforce the central role for Cic in SCA1 cerebellar pathophysiology and suggest that only modest reductions in Cic are needed to have profound therapeutic impact in SCA1.
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http://dx.doi.org/10.1093/hmg/ddaa212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689299PMC
November 2020

Dysphagia in spinocerebellar ataxias type 1, 2, 3 and 6.

J Neurol Sci 2020 Aug 4;415:116878. Epub 2020 May 4.

Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Initiative for Columbia Ataxia and Tremor, Columbia University, New York, NY, USA. Electronic address:

Background: Dysphagia is a common symptom and may be a cause of death in patients with spinocerebellar ataxias (SCAs). However, little is known about at which disease stage dysphagia becomes clinically relevant. Therefore, our study aims to investigate the prevalence of dysphagia in different disease stages of SCA 1, 2, 3 and 6.

Methods: We studied 237 genetically confirmed patients with SCA 1, 2, 3, 6 from the Clinical Research Consortium for SCAs and investigated the prevalence of self-reported dysphagia and the association between dysphagia and other clinical characteristics. We further stratified ataxia severity and studied the prevalence of dysphagia at each disease stage.

Results: Dysphagia was present in 59.9% of SCA patients. Patients with dysphagia had a longer disease duration and more severe ataxia than patients without dysphagia (patients with dysphagia vs. without dysphagia, disease duration (years): 14.51 ± 8.91 vs. 11.22 ± 7.82, p = .001, scale for the assessment and rating of ataxia [SARA]: 17.90 ± 7.74 vs. 13.04 ± 7.51, p = .000). Dysphagia was most common in SCA1, followed by SCA3, SCA 6, and SCA 2. Dysphagia in SCA1 and 3 was associated robustly with ataxia severity, whereas this association was less obvious in SCA2 and 6, demonstrating genotype-specific clinical variation.

Conclusion: Dysphagia is a common clinical symptom in SCAs, especially in the severe disease stage. Understanding dysphagia in SCA patients can improve the care of these patients and advance knowledge on the roles of the cerebellum and brainstem control in swallowing.
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http://dx.doi.org/10.1016/j.jns.2020.116878DOI Listing
August 2020

Staufen 1 amplifies proapoptotic activation of the unfolded protein response.

Cell Death Differ 2020 Oct 15;27(10):2942-2951. Epub 2020 May 15.

Department of Neurology, University of Utah, 175 North Medical Drive East, 5th Floor, Salt Lake City, UT, 84132, USA.

Staufen-1 (STAU1) is an RNA-binding protein that becomes highly overabundant in numerous neurodegenerative disease models, including those carrying mutations in presenilin1 (PSEN1), microtubule-associated protein tau (MAPT), huntingtin (HTT), TAR DNA-binding protein-43 gene (TARDBP), or C9orf72. We previously reported that elevations in STAU1 determine autophagy defects and its knockdown is protective in models of several neurodegenerative diseases. Additional functional consequences of STAU1 overabundance, however, have not been investigated. We studied the role of STAU1 in the chronic activation of the unfolded protein response (UPR), a common feature among neurodegenerative diseases and often directly associated with neuronal death. Here we report that STAU1 is a novel modulator of the UPR, and is required for apoptosis induced by activation of the PERK-CHOP pathway. STAU1 levels increased in response to multiple endoplasmic reticulum (ER) stressors, and exogenous expression of STAU1 was sufficient to cause apoptosis through the PERK-CHOP pathway of the UPR. Cortical neurons and skin fibroblasts derived from Stau1 mice showed reduced UPR and apoptosis when challenged with thapsigargin. In fibroblasts from individuals with SCA2 or with ALS-causing TDP-43 and C9ORF72 mutations, we found highly increased STAU1 and CHOP levels in basal conditions, and STAU1 knockdown restored CHOP levels to normal. Taken together, these results show that STAU1 overabundance reduces cellular resistance to ER stress and precipitates apoptosis.
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http://dx.doi.org/10.1038/s41418-020-0553-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492261PMC
October 2020

BraInMap Elucidates the Macromolecular Connectivity Landscape of Mammalian Brain.

Cell Syst 2020 04;10(4):333-350.e14

Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology and Harvard University, Boston, MA, USA.

Connectivity webs mediate the unique biology of the mammalian brain. Yet, while cell circuit maps are increasingly available, knowledge of their underlying molecular networks remains limited. Here, we applied multi-dimensional biochemical fractionation with mass spectrometry and machine learning to survey endogenous macromolecules across the adult mouse brain. We defined a global "interactome" comprising over one thousand multi-protein complexes. These include hundreds of brain-selective assemblies that have distinct physical and functional attributes, show regional and cell-type specificity, and have links to core neurological processes and disorders. Using reciprocal pull-downs and a transgenic model, we validated a putative 28-member RNA-binding protein complex associated with amyotrophic lateral sclerosis, suggesting a coordinated function in alternative splicing in disease progression. This brain interaction map (BraInMap) resource facilitates mechanistic exploration of the unique molecular machinery driving core cellular processes of the central nervous system. It is publicly available and can be explored here https://www.bu.edu/dbin/cnsb/mousebrain/.
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http://dx.doi.org/10.1016/j.cels.2020.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938770PMC
April 2020

ALS-associated genes in SCA2 mouse spinal cord transcriptomes.

Hum Mol Genet 2020 06;29(10):1658-1672

Department of Neurology, University of Utah, 175 North Medical Drive East, 5th Floor, Salt Lake City, UT 84132, USA.

The spinocerebellar ataxia type 2 (SCA2) gene ATXN2 has a prominent role in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS). In addition to cerebellar ataxia, motor neuron disease is often seen in SCA2, and ATXN2 CAG repeat expansions in the long normal range increase ALS risk. Also, lowering ATXN2 expression in TDP-43 ALS mice prolongs their survival. Here we investigated the ATXN2 relationship with motor neuron dysfunction in vivo by comparing spinal cord (SC) transcriptomes reported from TDP-43 and SOD1 ALS mice and ALS patients with those from SCA2 mice. SC transcriptomes were determined using an SCA2 bacterial artificial chromosome mouse model expressing polyglutamine expanded ATXN2. SCA2 cerebellar transcriptomes were also determined, and we also investigated the modification of gene expression following treatment of SCA2 mice with an antisense oligonucleotide (ASO) lowering ATXN2 expression. Differentially expressed genes (DEGs) defined three interconnected pathways (innate immunity, fatty acid biosynthesis and cholesterol biosynthesis) in separate modules identified by weighted gene co-expression network analysis. Other key pathways included the complement system and lysosome/phagosome pathways. Of all DEGs in SC, 12.6% were also dysregulated in the cerebellum. Treatment of mice with an ATXN2 ASO also modified innate immunity, the complement system and lysosome/phagosome pathways. This study provides new insights into the underlying molecular basis of SCA2 SC phenotypes and demonstrates annotated pathways shared with TDP-43 and SOD1 ALS mice and ALS patients. It also emphasizes the importance of ATXN2 in motor neuron degeneration and confirms ATXN2 as a therapeutic target.
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http://dx.doi.org/10.1093/hmg/ddaa072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322574PMC
June 2020

Neural selectivity, efficiency, and dose equivalence in deep brain stimulation through pulse width tuning and segmented electrodes.

Brain Stimul 2020 Jul - Aug;13(4):1040-1050. Epub 2020 Apr 9.

University of Utah Department of Biomedical Engineering, Salt Lake City, UT, USA.

Background: Achieving deep brain stimulation (DBS) dose equivalence is challenging, especially with pulse width tuning and directional contacts. Further, the precise effects of pulse width tuning are unknown, and recent reports of the effects of pulse width tuning on neural selectivity are at odds with classic biophysical studies.

Methods: We created multicompartment neuron models for two axon diameters and used finite element modeling to determine extracellular influence from standard and segmented electrodes. We analyzed axon activation profiles and calculated volumes of tissue activated.

Results: We find that long pulse widths focus the stimulation effect on small, nearby fibers, suppressing distant white matter tract activation (responsible for some DBS side effects) and improving battery utilization when equivalent activation is maintained for small axons. Directional leads enable similar benefits to a greater degree. Reexamining previous reports of short pulse stimulation reducing side effects, we explore a possible alternate explanation: non-dose equivalent stimulation may have resulted in reduced spread of neural activation. Finally, using internal capsule avoidance as an example in the context of subthalamic stimulation, we present a patient-specific model to show how long pulse widths could help increase the biophysical therapeutic window.

Discussion: We find agreement with classic studies and predict that long pulse widths may focus the stimulation effect on small, nearby fibers and improve power consumption. While future pre-clinical and clinical work is necessary regarding pulse width tuning, it is clear that future studies must ensure dose equivalence, noting that energy- and charge-equivalent amplitudes do not result in equivalent spread of neural activation when changing pulse width.
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http://dx.doi.org/10.1016/j.brs.2020.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308191PMC
December 2020

The impact of ethnicity on the clinical presentations of spinocerebellar ataxia type 3.

Parkinsonism Relat Disord 2020 03 17;72:37-43. Epub 2020 Feb 17.

Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA. Electronic address:

Background: For a variety of sporadic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, it is well-established that ethnicity does affect the disease phenotypes. However, how ethnicity contributes to the clinical symptoms and disease progressions in monogenetic disorders, such as spinocerebellar ataxia type 3 (SCA3), remains less studied.

Methods: We used multivariable linear and logistical regression models in 257 molecularly-confirmed SCA3 patients (66 Caucasians, 43 African Americans, and 148 Asians [composed of 131 Chinese and 17 Asian Americans]) to explore the influence of ethnicity on age at onset (AAO), ataxia severity, and non-ataxia symptoms (i.e. depression, tremor, and dystonia).

Results: We found that Asians had significantly later AAO, compared to Caucasians (β = 4.75, p = 0.000) and to African Americans (β = 6.64, p = 0.000) after adjusting for the pathological CAG repeat numbers in ATXN3. African Americans exhibited the most severe ataxia as compared to Caucasians (β = 3.81, p = 0.004) and Asians (β = 4.39, p = 0.001) after taking into consideration of the pathological CAG repeat numbers in ATXN3 and disease duration. Caucasians had a higher prevalence of depression than African Americans (β = 1.23, p = 0.040). Ethnicity had no influence on tremor or dystonia.

Conclusions: Ethnicity plays an important role in clinical presentations of SCA3 patients, which could merit further clinical studies and public health consideration. These results highlight the role of ethnicity in monogenetic, neurodegenerative disorders.
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http://dx.doi.org/10.1016/j.parkreldis.2020.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160000PMC
March 2020

Receptor protein tyrosine phosphatases control Purkinje neuron firing.

Cell Cycle 2020 01 26;19(2):153-159. Epub 2019 Dec 26.

Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA.

Spinocerebellar ataxias (SCA) are a genetically heterogeneous family of cerebellar neurodegenerative diseases characterized by abnormal firing of Purkinje neurons and degeneration. We recently demonstrated the slowed firing rates seen in several SCAs share a common etiology of hyper-activation of the Src family of non-receptor tyrosine kinases (SFKs). However, the lack of clinically available neuroactive SFK inhibitors lead us to investigate alternative mechanisms to modulate SFK activity. Previous studies demonstrate that SFK activity can be enhanced by the removal of inhibitory phospho-marks by receptor-protein-tyrosine phosphatases (RPTPs). In this Extra View we show that MTSS1 inhibits SFK activity through the binding and inhibition of a subset of the RPTP family members, and lowering RPTP activity in cerebellar slices with peptide inhibitors increases the suppressed Purkinje neuron basal firing rates seen in two different SCA models. Together these results identify RPTPs as novel effectors of Purkinje neuron basal firing, extending the MTSS1/SFK regulatory circuit we previously described and expanding the therapeutic targets for SCA patients.
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http://dx.doi.org/10.1080/15384101.2019.1695995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961678PMC
January 2020

Antisense therapies for movement disorders.

Mov Disord 2019 08 8;34(8):1112-1119. Epub 2019 Jul 8.

Department of Neurology, University of Utah, 175 North Medical Drive East, 5th Floor, Salt Lake City, Utah, USA.

Currently, few disease-modifying therapies exist for degenerative movement disorders. Antisense oligonucleotides are small DNA oligonucleotides, usually encompassing ∼20 base pairs, that can potentially target any messenger RNA of interest. Antisense oligonucleotides often contain modifications to the phosphate backbone, the sugar moiety, and the nucleotide base. The development of antisense oligonucleotide therapies spinal muscular atrophy and Duchenne muscular dystrophy suggest potentially wide-ranging therapeutic applications for antisense oligonucleotides in neurology. Successes with these two diseases have heightened interest in academia and the pharmaceutical industry to develop antisense oligonucleotides for several movement disorders, including, spinocerebellar ataxias, Huntington's disease, and Parkinson's disease. Compared to small molecules, antisense oligonucleotide-based therapies have an advantage because the target disease gene sequence is the immediate path to identifying the therapeutically effective complementary antisense oligonucleotide. In this review we describe the different types of antisense oligonucleotide chemistries and their potential use for the treatment of human movement disorders. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27782DOI Listing
August 2019

[Antisense therapies for neurological diseases].

Authors:
Stefan-M Pulst

Nervenarzt 2019 Aug;90(8):781-786

Department of Neurology, University of Utah, CNC Building, 5th Floor, 175 N Medical Drive E, 84132, Salt Lake City, UT, USA.

Despite identification of many genes causing neurodegenerative diseases in the last decades, development of disease-modifying treatments has been slow. Antisense oligonucleotide (ASO) therapeutics for spinal muscular atrophy, Duchenne muscular dystrophy and transthyretin amyloidosis predict a robust future for ASOs in medicine. Perhaps the most significant advantage of ASO therapeutics over other small molecule approaches is that acquisition of the target sequence provides immediate knowledge of possible complementary oligonucleotide therapeutics. This review article describes the various types of ASOs, their therapeutic use and the current preclinical efforts to develop new ASO treatments.
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http://dx.doi.org/10.1007/s00115-019-0724-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730669PMC
August 2019

Current Opinions and Consensus for Studying Tremor in Animal Models.

Cerebellum 2019 Dec;18(6):1036-1063

Department of Neurology, Southern Illinois University School of Medicine, Springfield, IL, USA.

Tremor is the most common movement disorder; however, we are just beginning to understand the brain circuitry that generates tremor. Various neuroimaging, neuropathological, and physiological studies in human tremor disorders have been performed to further our knowledge of tremor. But, the causal relationship between these observations and tremor is usually difficult to establish and detailed mechanisms are not sufficiently studied. To overcome these obstacles, animal models can provide an important means to look into human tremor disorders. In this manuscript, we will discuss the use of different species of animals (mice, rats, fruit flies, pigs, and monkeys) to model human tremor disorders. Several ways to manipulate the brain circuitry and physiology in these animal models (pharmacology, genetics, and lesioning) will also be discussed. Finally, we will discuss how these animal models can help us to gain knowledge of the pathophysiology of human tremor disorders, which could serve as a platform towards developing novel therapies for tremor.
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http://dx.doi.org/10.1007/s12311-019-01037-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872927PMC
December 2019

Antisense oligonucleotides: A primer.

Neurol Genet 2019 Apr 1;5(2):e323. Epub 2019 Apr 1.

Department of Neurology (D.R.S., S.M.P.), University of Utah, Salt Lake City, UT; and Center for the Science of Therapeutics (E.V.M.), Broad Institute of MIT and Harvard, Cambridge, MA.

There are few disease-modifying therapeutics for neurodegenerative diseases, but successes on the development of antisense oligonucleotide (ASO) therapeutics for spinal muscular atrophy and Duchenne muscular dystrophy predict a robust future for ASOs in medicine. Indeed, existing pipelines for the development of ASO therapies for spinocerebellar ataxias, Huntington disease, Alzheimer disease, amyotrophic lateral sclerosis, Parkinson disease, and others, and increased focus by the pharmaceutical industry on ASO development, strengthen the outlook for using ASOs for neurodegenerative diseases. Perhaps the most significant advantage to ASO therapeutics over other small molecule approaches is that acquisition of the target sequence provides immediate knowledge of putative complementary oligonucleotide therapeutics. In this review, we describe the various types of ASOs, how they are used therapeutically, and the present efforts to develop new ASO therapies that will contribute to a forthcoming toolkit for treating multiple neurodegenerative diseases.
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http://dx.doi.org/10.1212/NXG.0000000000000323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501637PMC
April 2019

Deep cerebellar stimulation reduces ataxic motor symptoms in the shaker rat.

Ann Neurol 2019 05;85(5):681-690

Department of Neurology.

Objective: Degenerative cerebellar ataxias (DCAs) affect up to 1 in 5,000 people worldwide, leading to incoordination, tremor, and falls. Loss of Purkinje cells, nearly universal across DCAs, dysregulates the dentatothalamocortical network. To address the paucity of treatment strategies, we developed an electrical stimulation-based therapy for DCAs targeting the dorsal dentate nucleus.

Methods: We tested this therapeutic strategy in the Wistar Furth shaker rat model of Purkinje cell loss resulting in tremor and ataxia. We implanted shaker rats with stimulating electrodes targeted to the dorsal dentate nucleus and tested a spectrum of frequencies ranging from 4 to 180 Hz.

Results: Stimulation at 30 Hz most effectively reduced motor symptoms. Stimulation frequencies >100 Hz, commonly used for parkinsonism and essential tremor, worsened incoordination, and frequencies within the tremor physiologic range may worsen tremor.

Interpretation: Low-frequency deep cerebellar stimulation may provide a novel strategy for treating motor symptoms of degenerative cerebellar ataxias. Ann Neurol 2019;85:681-690.
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http://dx.doi.org/10.1002/ana.25464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098166PMC
May 2019

Tremor in the Degenerative Cerebellum: Towards the Understanding of Brain Circuitry for Tremor.

Cerebellum 2019 Jun;18(3):519-526

Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Cerebellar degenerative pathology has been identified in tremor patients; however, how the degenerative pathology could contribute to tremor remains unclear. If the cerebellar degenerative pathology can directly drive tremor, one would hypothesize that tremor is likely to occur in the diseases of cerebellar ataxia and follows the disease progression in such disorders. To further test this hypothesis, we studied the occurrence of tremor in different disease stages of classical cerebellar degenerative disorders: spinocerebellar ataxias (SCAs). We further separately analyzed postural tremor and rest tremor, two forms of tremor that both involve the cerebellum. We also explored tremor in different subtypes of SCAs. We found that 18.1% of SCA patients have tremor. Interestingly, SCA patients with tremor have worse ataxia than those without tremor. When stratifying patients into mild, moderate, and severe disease stages according to the severity of ataxia, moderate and severe SCA patients more commonly have tremor than those with mild ataxia, the effect most prominently observed in postural tremor of SCA3 and SCA6 patients. Finally, tremor can independently contribute to worse functional status in SCA2 patients, even after adjusting for ataxia severity. Tremor is more likely to occur in the severe stage of cerebellar degeneration when compared to mild stages. Our results partially support the cerebellar degenerative model of tremor.
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http://dx.doi.org/10.1007/s12311-019-01016-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520148PMC
June 2019

The complex structure of genetic variation.

Authors:
Stefan M Pulst

Neurol Genet 2018 Dec 6;4(6):e299. Epub 2018 Dec 6.

Department of Neurology, University of Utah, Salt Lake City, UT.

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http://dx.doi.org/10.1212/NXG.0000000000000299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290488PMC
December 2018

MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias.

Proc Natl Acad Sci U S A 2018 12 7;115(52):E12407-E12416. Epub 2018 Dec 7.

Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305;

The genetically heterogeneous spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of nonreceptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-metastasis (MTSS1) is an ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically approved Src inhibitor corrects Purkinje neuron basal firing and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression.
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http://dx.doi.org/10.1073/pnas.1816177115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310854PMC
December 2018

Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration.

Nat Commun 2018 09 7;9(1):3648. Epub 2018 Sep 7.

Department of Neurology, University of Utah, 175 North Medical Drive East, 5th Floor, Salt Lake City, Utah 84132, USA.

Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by expansion of polyglutamine tract in the ATXN2 protein. We identified Staufen1 (STAU1) as an interactor of ATXN2, and showed elevation in cells from SCA2 patients, amyotrophic lateral sclerosis (ALS) patients, and in SCA2 mouse models. We demonstrated recruitment of STAU1 to mutant ATXN2 aggregates in brain tissue from patients with SCA2 human brain and in an SCA2 mouse model, and association of STAU1 elevation with dysregulation of SCA2-related transcript abundances. Targeting STAU1 in vitro by RNAi restored PCP2 transcript levels and lowering mutant ATXN2 also normalized STAU1 levels. Reduction of Stau1 in vivo improved motor behavior in an SCA2 mouse model, normalized the levels of several SCA2-related proteins, and reduced aggregation of polyglutamine-expanded ATXN2. These findings suggest a function for STAU1 in aberrant RNA metabolism associated with ATXN2 mutation, suggesting STAU1 is a possible novel therapeutic target for SCA2.
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http://dx.doi.org/10.1038/s41467-018-06041-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128856PMC
September 2018

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.

Neuron 2018 03;97(6):1268-1283.e6

Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
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http://dx.doi.org/10.1016/j.neuron.2018.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867896PMC
March 2018

Oligonucleotide therapeutics in neurodegenerative diseases.

RNA Biol 2018 1;15(6):707-714. Epub 2018 Jun 1.

a Department of Neurology , University of Utah , Salt Lake City , UT , USA.

Therapeutics that directly target RNAs are promising for a broad spectrum of disorders, including the neurodegenerative diseases. This is exemplified by the FDA approval of Nusinersen, an antisense oligonucleotide (ASO) therapeutic for spinal muscular atrophy (SMA). RNA targeting therapeutics are currently under development for amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and spinocerebellar ataxias. We have used an ASO approach toward developing a treatment for spinocerebellar ataxia type 2 (SCA2), for targeting the causative gene ATXN2. We demonstrated that reduction of ATXN2 expression in SCA2 mice treated by intracerebroventicular injection (ICV) of ATXN2 ASO delayed motor phenotype onset, improved the expression of several genes demonstrated abnormally reduced by transcriptomic profiling of SCA2 mice, and restored abnormal Purkinje cell firing frequency in acute cerebellar sections. Here we discuss RNA abnormalities in disease and the prospects of targeting neurodegenerative diseases at the level of RNA control using ASOs and other RNA-targeted therapeutics.
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http://dx.doi.org/10.1080/15476286.2018.1454812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152438PMC
November 2018

2017 Year in Review and Message from the Editors to Our Reviewers.

Neurol Genet 2018 Feb 16;4(1):e221. Epub 2018 Feb 16.

Department of Neurology (S.M.P., N.E.J.), University of Utah, Salt Lake City; Hôpital Erasme (M.P.), Université Libre de Bruxelles, Belgium; University of Chicago Medical Center (R.P.R.); and University of Miami (J.M.V.), Coral Gables, FL.

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http://dx.doi.org/10.1212/NXG.0000000000000221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852863PMC
February 2018

Protein kinase C activity is a protective modifier of Purkinje neuron degeneration in cerebellar ataxia.

Hum Mol Genet 2018 04;27(8):1396-1410

Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Among the many types of neurons expressing protein kinase C (PKC) enzymes, cerebellar Purkinje neurons are particularly reliant on appropriate PKC activity for maintaining homeostasis. The importance of PKC enzymes in Purkinje neuron health is apparent as mutations in PRKCG (encoding PKCγ) cause cerebellar ataxia. PRKCG has also been identified as an important node in ataxia gene networks more broadly, but the functional role of PKC in other forms of ataxia remains unexplored, and the mechanisms by which PKC isozymes regulate Purkinje neuron health are not well understood. Here, we investigated how PKC activity influences neurodegeneration in inherited ataxia. Using mouse models of spinocerebellar ataxia type 1 (SCA1) and 2 (SCA2) we identify an increase in PKC-mediated substrate phosphorylation in two different forms of inherited cerebellar ataxia. Normalizing PKC substrate phosphorylation in SCA1 and SCA2 mice accelerates degeneration, suggesting that the increased activity observed in these models is neuroprotective. We also find that increased phosphorylation of PKC targets limits Purkinje neuron membrane excitability, suggesting that PKC activity may support Purkinje neuron health by moderating excitability. These data suggest a functional role for PKC enzymes in ataxia gene networks, and demonstrate that increased PKC activity is a protective modifier of degeneration in inherited cerebellar ataxia.
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http://dx.doi.org/10.1093/hmg/ddy050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251693PMC
April 2018