Publications by authors named "Kathy L Newell"

Neurodegenerative diseases are characterized by the abnormal filamentous assembly of specific proteins in the central nervous system. Human genetic studies have established a causal role for protein assembly in neurodegeneration. However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases.

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Article Synopsis
  • Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease linked to abnormal tau protein accumulation, and previous studies were limited in exploring rare genetic variants due to the use of genotype arrays.* -
  • In this study, whole genome sequencing (WGS) on a large cohort allowed researchers to confirm known genetic loci related to PSP and discover new associations, particularly highlighting a different role for the APOE ε2 allele compared to Alzheimer's disease.* -
  • The findings expand knowledge of PSP's genetic underpinnings and identify potential targets for future research into the disease's mechanisms and treatments.*
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Neurodegenerative diseases are characterised by the abnormal filamentous assembly of specific proteins in the central nervous system . Human genetic studies established a causal role for protein assembly in neurodegeneration . However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases.

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Pathogenic variants in the UBQLN2 gene cause X-linked dominant amyotrophic lateral sclerosis and/or frontotemporal dementia characterized by ubiquilin 2 aggregates in neurons of the motor cortex, hippocampus and spinal cord. However, ubiquilin 2 neuropathology is also seen in sporadic and familial amyotrophic lateral sclerosis and/or frontotemporal dementia cases not caused by UBQLN2 pathogenic variants, particularly C9orf72-linked cases. This makes the mechanistic role of mutant ubiquilin 2 protein and the value of ubiquilin 2 pathology for predicting genotype unclear.

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Adult individuals with Down syndrome (DS) develop Alzheimer disease (AD). Whether there is a difference between AD in DS and AD regarding the structure of amyloid-β (Aβ) and tau filaments is unknown. Here we report the structure of Aβ and tau filaments from two DS brains.

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Importance: The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.

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Article Synopsis
  • Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease linked to tau protein accumulation, and previous studies using genotype arrays overlooked important genetic variations like rare variants and structural changes.* -
  • This study utilized whole genome sequencing (WGS) involving 1,718 PSP patients and 2,944 controls, confirming known genetic markers and discovering new associations, including the unique role of the ε2 allele as a risk factor.* -
  • The findings from this research advance the understanding of PSP genetics, highlighting potential new targets for disease mechanisms and treatment strategies.*
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Dementia with Lewy bodies (DLB) is a common form of dementia in the elderly population. We performed genome-wide DNA methylation mapping of cerebellar tissue from pathologically confirmed DLB cases and controls to study the epigenetic profile of this understudied disease. After quality control filtering, 728,197 CpG-sites in 278 cases and 172 controls were available for the analysis.

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Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of dementia after Alzheimer's disease, and is often also associated with motor disorders. The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins. In the majority of cases the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterizing different FTLD subtypes.

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We used electron cryo-microscopy (cryo-EM) to determine the structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer's disease and cerebral amyloid angiopathy. In agreement with previously reported structures, which were solved to a resolution of 4.4 Å, we found three types of filaments.

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It is increasingly evident that the association of glycans with the prion protein (PrP), a major post-translational modification, significantly impacts the pathogenesis of prion diseases. A recent bioassay study has provided evidence that the presence of PrP glycans decreases spongiform degeneration and disease-related PrP (PrPD) deposition in a murine model. We challenged (PRNPN181Q/197Q) transgenic (Tg) mice expressing glycan-free human PrP (TgGlyc-), with isolates from sporadic Creutzfeldt-Jakob disease subtype MM2 (sCJDMM2), sporadic fatal insomnia and familial fatal insomnia, three human prion diseases that are distinct but share histotypic and PrPD features.

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Introduction: We assessed TAR DNA-binding protein 43 (TDP-43) seeding activity and aggregates detection in olfactory mucosa of patients with frontotemporal lobar degeneration with TDP-43-immunoreactive pathology (FTLD-TDP) by TDP-43 seeding amplification assay (TDP43-SAA) and immunocytochemical analysis.

Methods: The TDP43-SAA was optimized using frontal cortex samples from 16 post mortem cases with FTLD-TDP, FTLD with tau inclusions, and controls. Subsequently, olfactory mucosa samples were collected from 17 patients with FTLD-TDP, 15 healthy controls, and three patients carrying MAPT variants.

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The abnormal assembly of TAR DNA-binding protein 43 (TDP-43) in neuronal and glial cells characterizes nearly all cases of amyotrophic lateral sclerosis (ALS) and around half of cases of frontotemporal lobar degeneration (FTLD). A causal role for TDP-43 assembly in neurodegeneration is evidenced by dominantly inherited missense mutations in TARDBP, the gene encoding TDP-43, that promote assembly and give rise to ALS and FTLD. At least four types (A-D) of FTLD with TDP-43 pathology (FTLD-TDP) are defined by distinct brain distributions of assembled TDP-43 and are associated with different clinical presentations of frontotemporal dementia.

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Two siblings with deletion mutation ∆K281 in MAPT developed frontotemporal dementia. At autopsy, numerous inclusions of hyperphosphorylated 3R Tau were present in neurons and glial cells of neocortex and some subcortical regions, including hippocampus, caudate/putamen and globus pallidus. The inclusions were argyrophilic with Bodian silver, but not with Gallyas-Braak silver.

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Hyaline protoplasmic astrocytopathy (HPA) describes a rare histologic finding of eosinophilic, hyaline cytoplasmic inclusions in astrocytes, predominantly in the cerebral cortex. It has mainly been observed in children and adults with a history of developmental delay and epilepsy, frequently with focal cortical dysplasia (FCD), but the nature and significance of these inclusions are unclear. In this study, we review the clinical and pathologic features of HPA and characterize the inclusions and brain tissue in which they are seen in surgical resection specimens from five patients with intractable epilepsy and HPA compared to five patients with intractable epilepsy without HPA using immunohistochemistry for filamin A, previously shown to label these inclusions, and a variety of astrocytic markers including aldehyde dehydrogenase 1 family member L1 (ALDH1L1), SRY-Box Transcription Factor 9 (SOX9), and glutamate transporter 1/excitatory amino acid transporter 2 (GLT-1/EAAT2) proteins.

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Alzheimer's disease (AD) is a looming public health disaster with limited interventions. Alzheimer's is a complex disease that can present with or without causative mutations and can be accompanied by a range of age-related comorbidities. This diverse presentation makes it difficult to study molecular changes specific to AD.

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Background: Neuroinflammation is an important feature of Alzheimer's disease (AD). Understanding which aspects of the immune system are important in AD may lead to new therapeutic approaches. We study the major histocompatibility complex class I-related immune molecule, MR1, which is recognized by an innate-like T cell population called mucosal-associated invariant T (MAIT) cells.

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An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories.

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Neurocytomas are rare low-grade brain tumors predominantly affecting young adults, but their cellular origin and molecular pathogenesis is largely unknown. We previously reported a sellar neurocytoma that secreted excess arginine vasopressin causing syndrome of inappropriate anti-diuretic hormone (SIADH). Whole exome sequencing in 21 neurocytoma tumor tissues identified somatic mutations in the in 3/21 (14%) tumors.

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Article Synopsis
  • Multiple System Atrophy (MSA) is a rare neurodegenerative disease characterized by abnormal protein aggregation and leads to motor and autonomic dysfunction.
  • Previous genetic studies didn’t find variants linked to MSA, prompting researchers to focus on autopsy-confirmed cases rather than merely clinical diagnoses.
  • The study identified significant genetic markers associated with MSA (located on chromosomes 3, 4, and 8), particularly highlighting the potential role of the ZIC4 gene in neuron vulnerability, especially in patients with different MSA types.
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Aims: Frontotemporal dementias are neuropathologically characterised by frontotemporal lobar degeneration (FTLD). Intraneuronal inclusions of transactive response DNA-binding protein 43 kDa (TDP-43) are the defining pathological hallmark of approximately half of the FTLD cases, being referred to as FTLD-TDP. The classification of FTLD-TDP into five subtypes (Type A to Type E) is based on pathologic phenotypes; however, the molecular determinants underpinning the phenotypic heterogeneity of FTLD-TDP are not well known.

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Many age-dependent neurodegenerative diseases, such as Alzheimer's and Parkinson's, are characterized by abundant inclusions of amyloid filaments. Filamentous inclusions of the proteins tau, amyloid-β, α-synuclein and transactive response DNA-binding protein (TARDBP; also known as TDP-43) are the most common. Here we used structure determination by cryogenic electron microscopy to show that residues 120-254 of the lysosomal type II transmembrane protein 106B (TMEM106B) also form amyloid filaments in human brains.

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