Jill M. Weimer's research while affiliated with University of Sioux Falls and other places

Publications (49)

Article
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Background CLN8-Batten disease (CLN8 disease) is a rare neurodegenerative disorder characterized phenotypically by progressive deterioration of motor and cognitive abilities, visual symptoms, epileptic seizures, and premature death. Mutations in CLN8 results in characteristic Batten disease symptoms and brain-wide pathology including accumulation o...
Preprint
Innate lymphoid cells (ILCs) are rare tissue-resident “helper” lymphocytes that do not express diversified antigen receptors. Type 3 ILCs (ILC3s) are an important class of these cells enriched in the respiratory and intestinal mucosa, where they regulate inflammation and mucosal homeostasis. To gain insight into the cis-regulatory circuitries under...
Preprint
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Mouse models of CLN3 Batten disease, a rare lysosomal storage disorder with no cure, have improved our understanding of CLN3 biology and therapeutics through their ease of use and a consistent display of cellular pathology. However, the translatability of murine models is limited by disparities in anatomy, body size, life span, and inconsistent, su...
Article
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Model organism (MO) research provides a basic understanding of biology and disease due to the evolutionary conservation of the molecular and cellular language of life. MOs have been used to identify and understand the function of orthologous genes, proteins, cells and tissues involved in biological processes, to develop and evaluate techniques and...
Article
CLN2 Batten disease is a lysosomal disorder in which pathogenic variants in CLN2 lead to reduced activity in the enzyme tripeptidyl peptidase 1. The disease typically manifests around 2 to 4 years of age with developmental delay, ataxia, seizures, inability to speak and walk, and fatality between 6 and 12 years of age. Multiple Cln2 mouse models ex...
Article
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Introduction CLN3 Batten disease is a rare pediatric neurodegenerative lysosomal disorder caused by biallelic disease-associated variants in CLN3. Despite decades of intense research, specific biofluid biomarkers of disease status have not been reported, hindering clinical development of therapies. Thus, we sought to determine whether individuals w...
Article
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Batten disease is unique among lysosomal storage disorders for the early and profound manifestation in the central nervous system, but little is known regarding potential neuron-specific roles for the disease-associated proteins. We demonstrate substantial overlap in the protein interactomes of three transmembrane Batten proteins (CLN3, CLN6, and C...
Article
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CLN7 Batten disease, also known as variant late infantile neuronal ceroid lipofuscinosis type 7 (vLINCL7), is an ultra-rare form of Batten disease that presents early in life with severe neurological symptoms, including visual deficits, motor problems, and frequent seizures. There is high unmet need for disease-modifying therapies, as no existing t...
Article
Ependymal cells (ECs) line the ventricular surfaces of the mammalian central nervous system (CNS) and their development is indispensable to structural integrity and functions of the CNS. We previously reported that EC-specific genetic deletion of the myristoylated alanine-rich protein kinase C substrate (Marcks) disrupts barrier functions and eleva...
Article
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Background Commonly known as Batten disease, the neuronal ceroid lipofuscinoses (NCLs) are a genetically heterogeneous group of rare pediatric lysosomal storage disorders characterized by the intracellular accumulation of autofluorescent material (known as lipofuscin), progressive neurodegeneration, and neurological symptoms. In 2002, a disease-cau...
Article
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Pathogenic variants in CKAP2L have previously been reported in Filippi Syndrome (FS), a rare autosomal recessive, craniodigital syndrome characterized by microcephaly, syndactyly, short stature, intellectual disability, and dysmorphic facial features. To date, fewer than ten patients with pathogenic variants in CKAP2L associated with FS have been r...
Article
SEC24 is mainly involved in cargo sorting during COPII vesicle assembly. There are four SEC24 paralogs (A to D) in mammals, which are classified into two subgroups (SEC24A/B and SEC24C/D). Pathological mutations in SEC24D cause osteogenesis imperfecta with craniofacial dysplasia in humans. sec24d mutant fish also recapitulate the phenotypes. Consis...
Article
Batten disease is a family of rare, lysosomal disorders caused by mutations in one of at least 13 genes, which encode a diverse set of lysosomal and extralysosomal proteins. Despite decades of research, the development of effective therapies has remained intractable. But now, the field is experiencing rapid, unprecedented progress on multiple front...
Preprint
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As neurons establish extensive connections throughout the central nervous system, the transport of cargo along the microtubule network of the axon is crucial for differentiation and homeostasis. Specifically, building blocks such as membrane and cytoskeletal components, organelles, transmembrane receptors, adhesion molecules, and peptide neurotrans...
Preprint
Batten disease is unique among lysosomal storage disorders for the early and profound manifestation in the central nervous system, but little is known regarding potential neuron-specific roles for the disease-associated proteins. We demonstrate substantial overlap in the protein interactomes of three transmembrane Batten proteins (CLN3, CLN6, and C...
Article
Full-text available
Acid alpha-glucosidase (GAA) is a lysosomal glycogen-catabolizing enzyme, the deficiency of which leads to Pompe disease. Pompe disease can be treated with systemic recombinant human GAA (rhGAA) enzyme replacement therapy (ERT), but the current standard of care exhibits poor uptake in skeletal muscles, limiting its clinical efficacy. Further, it is...
Preprint
Procollagen requires COPII coat proteins for export from the endoplasmic reticulum (ER). SEC24 is the major component of the COPII proteins that selects cargo during COPII vesicle assembly. There are four paralogs (A to D) of SEC24 in mammals, which are classified into two subgroups. Pathological mutations in SEC24D cause osteogenesis imperfecta wi...
Article
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Mutations in CLN3 lead to photoreceptor cell loss in CLN3 disease, a lysosomal storage disorder characterized by childhood-onset vision loss, neurological impairment, and premature death. However, how CLN3 mutations cause photoreceptor cell death is not known. Here, we show that CLN3 is required for phagocytosis of photoreceptor outer segment (POS)...
Article
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Batten disease is a family of rare, fatal, neuropediatric diseases presenting with memory/learning decline, blindness, and loss of motor function. Recently, we reported the use of an AAV9-mediated gene therapy that prevents disease progression in a mouse model of CLN6-Batten disease (Cln6 nclf ), restoring lifespans in treated animals. Despite the...
Article
CLN8 disease is a rare form of neuronal ceroid lipofuscinosis caused by biallelic mutations in the CLN8 gene, which encodes a transmembrane endoplasmic reticulum protein involved in trafficking of lysosomal enzymes. CLN8 disease patients present with myoclonus, tonic-clonic seizures, and progressive declines in cognitive and motor function, with ma...
Article
Full-text available
CLN3 Batten disease is an autosomal recessive, neurodegenerative, lysosomal storage disease caused by mutations in CLN3, which encodes a lysosomal membrane protein1–3. There are no disease-modifying treatments for this disease that affects up to 1 in 25,000 births, has an onset of symptoms in early childhood and typically is fatal by 20–30 years of...
Article
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CLN3 Batten disease (CLN3 disease) is a pediatric lysosomal storage disorder that presents with progressive blindness, motor and cognitive decline, seizures, and premature death. CLN3 disease results from mutations in CLN3 with the most prevalent mutation, a 966 bp deletion spanning exons 7–8, affecting ~ 75% of patients. Mouse models with complete...
Article
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Lysosomal enzymes are synthesized in the endoplasmic reticulum (ER) and transferred to the Golgi complex by interaction with the Batten disease protein CLN8 (ceroid lipofuscinosis, neuronal, 8). Here we investigated the relationship of this pathway with CLN6, an ER-associated protein of unknown function that is defective in a different Batten disea...
Article
Due to their capacity to self-renew, proliferate and generate multi-lineage cells, adult-derived stem cells offer great potential in regenerative therapies to treat maladies such as diabetes, cardiac disease, neurological disorders and orthopedic injuries. Commonly derived from adipose tissue, the stromal vascular fraction (SVF), a heterogeneous ce...
Preprint
CLN8 disease is a rare form of neuronal ceroid lipofuscinosis caused by biallelic mutations in the CLN8 gene, which encodes a transmembrane endoplasmic reticulum protein involved in trafficking of lysosomal enzymes. CLN8 disease patients present with myoclonus, tonic-clonic seizures, and progressive declines in cognitive and motor function, with ma...
Preprint
Full-text available
Patients with densely innervated tumors do poorly as compared to those with sparsely innervated disease. Why some tumors heavily recruit nerves while others do not, remains unknown as does the functional contribution of tumor-infiltrating nerves to cancer. Moreover, while patients receive chemotherapeutic treatment, whether these drugs affect nerve...
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Article
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Neurofibromatosis type 1 (NF1) is a rare, autosomal dominant disease with variable clinical presentations. Large animal models are useful to help dissect molecular mechanisms, determine relevant biomarkers, and develop effective therapeutics. Here, we studied a NF1 minipig model (NF1+/ex42del) for the first 12 months of life to evaluate phenotype d...
Article
While research has accelerated the development of new treatments for pediatric neurodegenerative disorders, the ability to demonstrate the long-term efficacy of these therapies has been hindered by the lack of convincing, noninvasive methods for tracking disease progression both in animal models and in human clinical trials. Here, we unveil a new t...
Article
Purpose: Malignant peripheral nerve sheath tumors (MPNSTs) are deadly sarcomas that lack effective therapies. In most MPNSTs, the retinoblastoma (RB1) tumor suppressor is disabled by hyperactivation of cyclin dependent kinases (CDKs), commonly through loss of CDK inhibitory proteins such as p27(Kip1). RABL6A is an inhibitor of RB1 whose role in MP...
Article
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Genetically modified swine disease models are becoming increasingly important for studying molecular, physiological and pathological characteristics of human disorders. Given the limited history of these model systems, there remains a great need for proven molecular reagents in swine tissue. Here, to provide a resource for neurological models of di...
Article
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CLN3 mutations cause the fatal neurodegenerative disorder, CLN3 Batten disease. The Cln3−/− mouse model displays characteristic features of the human disease including motor deficits. When mice received acidified drinking water (pH 2.5–2.9) instead of normal tap water (pH 8.4) for several generations, the motor skills of Cln3−/− mice normalized to...
Data
Cerebellar layers of Cln2R207X/R207X mice display enhanced mitochondrial ATP synthase subunit c accumulation. Images of the molecular (ML) and granular (GL) cerebellar layers demonstrate accumulation of mitochondrial ATP synthase subunit c in Cln2R207X/R207X mice when compared to Cln2+/+ controls. Pronounced accumulation is present in the Purkinje...
Data
Unaltered sphingomyelinase activity and selectively altered PPT1 activity in various Cln2R207X/R207X mouse tissues. Fluorogenic enzyme activity assays for sphingomyelinase (A) and PPT1 (B) were used to measure endogenous activity in five different tissues from 1-month-old Cln2+/+ (n = 3) and Cln2R207X/R207X (n = 3) mice. In the sphingomyelinase act...
Data
No signs of activated microglia at 3 months in Cln2R207X/R207X mice. (A) Superficial and deep cortical layers from 3-month-old Cln2+/+ and Cln2R207X/R207X mice show minimal differences in immunostaining for the microglial marker, Iba1. (B) Images from 3-month-old Cln2+/+ (n = 4) and Cln2R207X/R207X (n = 5) mice were blindly collected and analyzed f...
Data
Similar levels of anxiety in Cln2+/+ and Cln2R207X/R207X mice. The light/dark box test was used to assess for anxiety in 3-month-old Cln2+/+ (n = 14) and Cln2R207X/R207X (n = 20) mice. Both cohorts spent similar amounts of time in the dark. Columns and bars represent mean ± SEM. Statistical significance was determined using an unpaired t-test. (TIF...
Data
A significant portion of mitochondrial ATP synthase subunit c accumulation is localized to the lysosome. Cln2R207X/R207X cerebral sections immunostained with anti-subunit c (red) and anti-LAMP-1 (green) reveal co-localization. (TIF)
Data
Hypereosinophilic inclusions and neurodegeneration in 4-month-old Cln2R207X/R207X mice. Tissues from Cln2+/+ (n = 3) and Cln2R207X/R207X (n = 3) mice were sectioned, hematoxylin/eosin stained, and evaluated by a veterinary pathologist under blinded conditions. The pathology report solely identified cerebral cellular hypereosinophilic inclusions (ar...

Citations

... Striving for integrity in science through openly accessible tools and resources can enable true advance in a given field and strengthen the translation of results to the clinic to benefit patients. Disease Models & Mechanisms (DMM)'s dedicated Resource articles report novel, or substantially improved, techniques, approaches, laboratory models, datasets (Cheng et al., 2022) or tools that are of significant use to a specific disease research community. In addition, rigorous validation of these advances is essential to a robust DMM Resource article to demonstrate its value in investigating disease mechanism and novel diagnostic or therapeutic approaches. ...
... To determine if CLN3 Δex7/8 miniswine recapitulate the cognitive decline displayed in CLN3 disease patients, animals were trained in a simple T-maze as previously described 32,48 . Briefly, the miniswine are allowed to roam the maze for four days for 10 minutes each day in the acclimation phase. ...
... For example, whole organ pathology may be monitored using magnetic resonance imaging (MRI) with the use of quantitative brain MRI [59] and cardiac MRI [60]. Cellular pathology can be investigated and monitored using electron microscopy [39,40,51], whilst abnormalities in small molecules and specific proteins can be evaluated using mass spectrometry [58,61]. ...
... Neuronal ceroid lipofuscinosis is a heterogeneous group of lysosomal storage disorders with a mainly autosomal recessive inheritance pattern, and a devastating outcome [1][2][3]. Since the first clinical description of cases compatible with neuronal ceroid lipofuscinosis in 1826, thirteen genes implicated in the disease have been identified, with approximately 446 disease-causing mutations reported to date [4]. Neuronal ceroid lipofuscinosis type 6 (NCL6) is caused by mutations in the gene CLN6, located in the chromosome 15q21-23 [5]. ...
... Collagens are the major component of the extracellular matrix (ECM). Type I and II procollagens form about 300 nm-long rigid triple helices (Bachinger et al., 1993;Bonfanti et al., 1998) and require COPII proteins for ER export (Boyadjiev et al., 2006;Garbes et al., 2015;Long et al., 2010;Lu and Kim, 2020;Lu et al., 2022;Ohisa et al., 2010;Sarmah et al., 2010;Townley et al., 2008;Zhu et al., 2015). Because COPII proteins typically generate vesicles of 60-80 nm in diameter, a mechanism must exist that allows COPII coat proteins to accommodate such large cargo molecules. ...
... NCLs have been subclassified according to age at onset and clinical features into congenital (CNCL), infantile (INCL), late-infantile (LINCL), juvenile (JNCL), and adult (ANCL) neuronal ceroid lipofuscinoses. Thirteen genes with NCL associated variants have been established to date, named CLN1-CLN8 and CLN10-CLN14 [10,11]. Additionally, a new subtype of NCL (CLN15) has been proposed [12]. ...
... Ceroid lipofuscinosis neuronal protein 6, encoded by the CLN6 gene, forms complexes with other proteins which act as key-regulators of vesicular sorting and trafficking. Defects can have a variety of consequences, from diminished lysosomal function to impaired neurotransmitter secretion and neurite outgrowth [14][15][16]. The worldwide incidence of CLN6 disease is currently not accurately known. ...
... The increase in MT velocity could suggest an increase in MT sliding or altered regulation or localization of polymerization-promoting MAPs such as CRMP2 (Nakamura et al., 2020). CRMP2 has been reported to influence MT polymerization and stabilization and has been found in complex with KLC4, supporting its potential role in KLC4mediated effects on MTs (Liz et al., 2014;Koh et al., 2021). The model of KLC4 as a mediator of microtubule dynamics is also supported by the similarities in phenotype between klc4 mutants and kinesore treatment. ...
... Gaa is synthesized as a 110 kDa glycoprotein and trafficked to the late endosome/lysosome from the trans-Golgi network via the mannose-6-phosphate receptor (25). Maturation of Gaa occurs in the endolysosome via N-glycan processing and proteolytic cleavage to generate two major active Gaa species (7,26). Gaa has been shown to cleave both α-1,4 glycosidic strands and α-1,6-glycosidic branch points of the glycogen molecule (13,14,27), with a higher efficiency for α-1,4-glycosidic bonds (28). ...
... Interestingly, a much more severe collagen secretion defect was observed in the yolk sac than in the embryo of Sec24d knockout mice. This tissue-specific phenotype was correlated with the absence of SEC24B in the yolk sac [50]. Thus, specific cargo molecules relevant to the phenotypes of a disease and tissue-specific expression profiles of SEC24 paralogs allow us to better understand the pathology of the disease. ...