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11 pages, 2174 KiB

Open AccessArticle

Susceptibility of Beavers to Chronic Wasting Disease

by Allen Herbst, Serene Wohlgemuth, Jing Yang, Andrew R. Castle, Diana Martinez Moreno, Alicia Otero, Judd M. Aiken, David Westaway and Debbie McKenzie

Biology 2022, 11(5), 667; https://doi.org/10.3390/biology11050667 - 26 Apr 2022

Cited by 1 | Viewed by 5250

Abstract

Chronic wasting disease (CWD) is a contagious, fatal, neurodegenerative prion disease of cervids. The expanding geographical range and rising prevalence of CWD are increasing the risk of pathogen transfer and spillover of CWD to non-cervid sympatric species. As beavers have close contact with [...] Read more.

Chronic wasting disease (CWD) is a contagious, fatal, neurodegenerative prion disease of cervids. The expanding geographical range and rising prevalence of CWD are increasing the risk of pathogen transfer and spillover of CWD to non-cervid sympatric species. As beavers have close contact with environmental and food sources of CWD infectivity, we hypothesized that they may be susceptible to CWD prions. We evaluated the susceptibility of beavers to prion diseases by challenging transgenic mice expressing beaver prion protein (tgBeaver) with five strains of CWD, four isolates of rodent-adapted prions and one strain of Creutzfeldt–Jakob disease. All CWD strains transmitted to the tgBeaver mice, with attack rates highest from moose CWD and the 116AG and H95+ strains of deer CWD. Mouse-, rat-, and especially hamster-adapted prions were also transmitted with complete attack rates and short incubation periods. We conclude that the beaver prion protein is an excellent substrate for sustaining prion replication and that beavers are at risk for CWD pathogen transfer and spillover. Full article

(This article belongs to the Special Issue Selective Vulnerability in Neurodegenerative Diseases)

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13 pages, 1980 KiB

Open AccessArticle

Selective Loss of MATR3 in Spinal Interneurons, Upper Motor Neurons and Hippocampal CA1 Neurons in a MATR3 S85C Knock-In Mouse Model of Amyotrophic Lateral Sclerosis

by Justin You, Katarina Maksimovic, Jooyun Lee, Mashiat Khan, Rintaro Masuda and Jeehye Park

Biology 2022, 11(2), 298; https://doi.org/10.3390/biology11020298 - 12 Feb 2022

Cited by 7 | Viewed by 3859

Abstract

The neuropathological hallmark of amyotrophic lateral sclerosis (ALS) is motor neuron degeneration in the spinal cord and cortex. Accumulating studies report that other neurons in the central nervous system (CNS) are also affected in ALS. Mutations in Matr3, which encodes a nuclear [...] Read more.

The neuropathological hallmark of amyotrophic lateral sclerosis (ALS) is motor neuron degeneration in the spinal cord and cortex. Accumulating studies report that other neurons in the central nervous system (CNS) are also affected in ALS. Mutations in Matr3, which encodes a nuclear matrix protein involved in RNA splicing, have been linked to ALS. Previously, we generated a MATR3 S85C knock-in (KI) mouse model that recapitulates early-stage features of ALS. We reported that MATR3 S85C KI mice exhibit defects in lumbar spinal cord motor neurons and in cerebellar Purkinje cells, which are associated with reduced MATR3 immunoreactivity. Here, we show that neurons in various other regions of the CNS are affected in MATR3 S85C KI mice. Using histological analyses, we found selective loss of MATR3 staining in α-motor neurons, but not γ-motor neurons in the cervical and thoracic spinal cord. Loss of MATR3 was also found in parvalbumin-positive interneurons in the cervical, thoracic and lumbar spinal cord. In addition, we found the loss of MATR3 in subsets of upper motor neurons and hippocampal CA1 neurons. Collectively, our findings suggest that these additional neuronal types may contribute to the disease process in MATR3 S85C KI mice. Full article

(This article belongs to the Special Issue Selective Vulnerability in Neurodegenerative Diseases)

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Review

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22 pages, 1931 KiB

Open AccessReview

Selective Vulnerability to Neurodegenerative Disease: Insights from Cell Type-Specific Translatome Studies

by Walker S. Jackson, Susanne Bauer, Lech Kaczmarczyk and Srivathsa S. Magadi

Biology 2024, 13(2), 67; https://doi.org/10.3390/biology13020067 - 23 Jan 2024

Cited by 2 | Viewed by 2711

Abstract

Neurodegenerative diseases (NDs) manifest a wide variety of clinical symptoms depending on the affected brain regions. Gaining insights into why certain regions are resistant while others are susceptible is vital for advancing therapeutic strategies. While gene expression changes offer clues about disease responses [...] Read more.

Neurodegenerative diseases (NDs) manifest a wide variety of clinical symptoms depending on the affected brain regions. Gaining insights into why certain regions are resistant while others are susceptible is vital for advancing therapeutic strategies. While gene expression changes offer clues about disease responses across brain regions, the mixture of cell types therein obscures experimental results. In recent years, methods that analyze the transcriptomes of individual cells (e.g., single-cell RNA sequencing or scRNAseq) have been widely used and have provided invaluable insights into specific cell types. Concurrently, transgene-based techniques that dissect cell type-specific translatomes (CSTs) in model systems, like RiboTag and bacTRAP, offer unique advantages but have received less attention. This review juxtaposes the merits and drawbacks of both methodologies, focusing on the use of CSTs in understanding conditions like amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Alzheimer’s disease (AD), and specific prion diseases like fatal familial insomnia (FFI), genetic Creutzfeldt–Jakob disease (gCJD), and acquired prion disease. We conclude by discussing the emerging trends observed across multiple diseases and emerging methods. Full article

(This article belongs to the Special Issue Selective Vulnerability in Neurodegenerative Diseases)

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13 pages, 535 KiB

Open AccessReview

Strain-Specific Targeting and Destruction of Cells by Prions

by Sara M. Simmons and Jason C. Bartz

Biology 2024, 13(1), 57; https://doi.org/10.3390/biology13010057 - 20 Jan 2024

Viewed by 2012

Abstract

Prion diseases are caused by the disease-specific self-templating infectious conformation of the host-encoded prion protein, PrP^Sc. Prion strains are operationally defined as a heritable phenotype of disease under controlled conditions. One of the hallmark phenotypes of prion strain diversity is tropism [...] Read more.

Prion diseases are caused by the disease-specific self-templating infectious conformation of the host-encoded prion protein, PrP^Sc. Prion strains are operationally defined as a heritable phenotype of disease under controlled conditions. One of the hallmark phenotypes of prion strain diversity is tropism within and between tissues. A defining feature of prion strains is the regional distribution of PrP^Sc in the CNS. Additionally, in both natural and experimental prion disease, stark differences in the tropism of prions in secondary lymphoreticular system tissues occur. The mechanism underlying prion tropism is unknown; however, several possible hypotheses have been proposed. Clinical target areas are prion strain-specific populations of neurons within the CNS that are susceptible to neurodegeneration following the replication of prions past a toxic threshold. Alternatively, the switch from a replicative to toxic form of PrP^Sc may drive prion tropism. The normal form of the prion protein, PrP^C, is required for prion formation. More recent evidence suggests that it can mediate prion and prion-like disease neurodegeneration. In vitro systems for prion formation have indicated that cellular cofactors contribute to prion formation. Since these cofactors can be strain specific, this has led to the hypothesis that the distribution of prion formation cofactors can influence prion tropism. Overall, there is evidence to support several mechanisms of prion strain tropism; however, a unified theory has yet to emerge. Full article

(This article belongs to the Special Issue Selective Vulnerability in Neurodegenerative Diseases)

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23 pages, 1873 KiB

Open AccessFeature PaperReview

The Contribution of the Locus Coeruleus–Noradrenaline System Degeneration during the Progression of Alzheimer’s Disease

by Dilek Mercan and Michael Thomas Heneka

Biology 2022, 11(12), 1822; https://doi.org/10.3390/biology11121822 - 14 Dec 2022

Cited by 13 | Viewed by 5575

Abstract

Alzheimer’s disease (AD), which is characterized by extracellular accumulation of amyloid-beta peptide and intracellular aggregation of hyperphosphorylated tau, is the most common form of dementia. Memory loss, cognitive decline and disorientation are the ultimate consequences of neuronal death, synapse loss and neuroinflammation in [...] Read more.

Alzheimer’s disease (AD), which is characterized by extracellular accumulation of amyloid-beta peptide and intracellular aggregation of hyperphosphorylated tau, is the most common form of dementia. Memory loss, cognitive decline and disorientation are the ultimate consequences of neuronal death, synapse loss and neuroinflammation in AD. In general, there are many brain regions affected but neuronal loss in the locus coeruleus (LC) is one of the earliest indicators of neurodegeneration in AD. Since the LC is the main source of noradrenaline (NA) in the brain, degeneration of the LC in AD leads to decreased NA levels, causing increased neuroinflammation, enhanced amyloid and tau burden, decreased phagocytosis and impairment in cognition and long-term synaptic plasticity. In this review, we summarized current findings on the locus coeruleus–noradrenaline system and consequences of its dysfunction which is now recognized as an important contributor to AD progression. Full article

(This article belongs to the Special Issue Selective Vulnerability in Neurodegenerative Diseases)

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34 pages, 2611 KiB

Open AccessReview

The Cell Autonomous and Non-Cell Autonomous Aspects of Neuronal Vulnerability and Resilience in Amyotrophic Lateral Sclerosis

by Christoph Schweingruber and Eva Hedlund

Biology 2022, 11(8), 1191; https://doi.org/10.3390/biology11081191 - 8 Aug 2022

Cited by 11 | Viewed by 5950

Abstract

Amyotrophic lateral sclerosis (ALS) is defined by the loss of upper motor neurons (MNs) that project from the cerebral cortex to the brain stem and spinal cord and of lower MNs in the brain stem and spinal cord which innervate skeletal muscles, leading [...] Read more.

Amyotrophic lateral sclerosis (ALS) is defined by the loss of upper motor neurons (MNs) that project from the cerebral cortex to the brain stem and spinal cord and of lower MNs in the brain stem and spinal cord which innervate skeletal muscles, leading to spasticity, muscle atrophy, and paralysis. ALS involves several disease stages, and multiple cell types show dysfunction and play important roles during distinct phases of disease initiation and progression, subsequently leading to selective MN loss. Why MNs are particularly vulnerable in this lethal disease is still not entirely clear. Neither is it fully understood why certain MNs are more resilient to degeneration in ALS than others. Brain stem MNs of cranial nerves III, IV, and VI, which innervate our eye muscles, are highly resistant and persist until the end-stage of the disease, enabling paralyzed patients to communicate through ocular tracking devices. MNs of the Onuf’s nucleus in the sacral spinal cord, that innervate sphincter muscles and control urogenital functions, are also spared throughout the disease. There is also a differential vulnerability among MNs that are intermingled throughout the spinal cord, that directly relate to their physiological properties. Here, fast-twitch fatigable (FF) MNs, which innervate type IIb muscle fibers, are affected early, before onset of clinical symptoms, while slow-twitch (S) MNs, that innervate type I muscle fibers, remain longer throughout the disease progression. The resilience of particular MN subpopulations has been attributed to intrinsic determinants and multiple studies have demonstrated their unique gene regulation and protein content in health and in response to disease. Identified factors within resilient MNs have been utilized to protect more vulnerable cells. Selective vulnerability may also, in part, be driven by non-cell autonomous processes and the unique surroundings and constantly changing environment close to particular MN groups. In this article, we review in detail the cell intrinsic properties of resilient and vulnerable MN groups, as well as multiple additional cell types involved in disease initiation and progression and explain how these may contribute to the selective MN resilience and vulnerability in ALS. Full article

(This article belongs to the Special Issue Selective Vulnerability in Neurodegenerative Diseases)

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27 pages, 1498 KiB

Open AccessReview

Regulating Phase Transition in Neurodegenerative Diseases by Nuclear Import Receptors

by Amandeep Girdhar and Lin Guo

Biology 2022, 11(7), 1009; https://doi.org/10.3390/biology11071009 - 4 Jul 2022

Cited by 7 | Viewed by 3763

Abstract

RNA-binding proteins (RBPs) with a low-complexity prion-like domain (PLD) can undergo aberrant phase transitions and have been implicated in neurodegenerative diseases such as ALS and FTD. Several nuclear RBPs mislocalize to cytoplasmic inclusions in disease conditions. Impairment in nucleocytoplasmic transport is another major [...] Read more.

RNA-binding proteins (RBPs) with a low-complexity prion-like domain (PLD) can undergo aberrant phase transitions and have been implicated in neurodegenerative diseases such as ALS and FTD. Several nuclear RBPs mislocalize to cytoplasmic inclusions in disease conditions. Impairment in nucleocytoplasmic transport is another major event observed in ageing and in neurodegenerative disorders. Nuclear import receptors (NIRs) regulate the nucleocytoplasmic transport of different RBPs bearing a nuclear localization signal by restoring their nuclear localization. NIRs can also specifically dissolve or prevent the aggregation and liquid–liquid phase separation of wild-type or disease-linked mutant RBPs, due to their chaperoning activity. This review focuses on the LLPS of intrinsically disordered proteins and the role of NIRs in regulating LLPS in neurodegeneration. This review also discusses the implication of NIRs as therapeutic agents in neurogenerative diseases. Full article

(This article belongs to the Special Issue Selective Vulnerability in Neurodegenerative Diseases)

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21 pages, 2577 KiB

Open AccessReview

Tau Post-Translational Modifications: Potentiators of Selective Vulnerability in Sporadic Alzheimer’s Disease

by Trae Carroll, Sanjib Guha, Keith Nehrke and Gail V. W. Johnson

Biology 2021, 10(10), 1047; https://doi.org/10.3390/biology10101047 - 15 Oct 2021

Cited by 20 | Viewed by 4299

Abstract

Sporadic Alzheimer’s Disease (AD) is the most common form of dementia, and its severity is characterized by the progressive formation of tau neurofibrillary tangles along a well-described path through the brain. This spatial progression provides the basis for Braak staging of the pathological [...] Read more.

Sporadic Alzheimer’s Disease (AD) is the most common form of dementia, and its severity is characterized by the progressive formation of tau neurofibrillary tangles along a well-described path through the brain. This spatial progression provides the basis for Braak staging of the pathological progression for AD. Tau protein is a necessary component of AD pathology, and recent studies have found that soluble tau species with selectively, but not extensively, modified epitopes accumulate along the path of disease progression before AD-associated insoluble aggregates form. As such, modified tau may represent a key cellular stressing agent that potentiates selective vulnerability in susceptible neurons during AD progression. Specifically, studies have found that tau phosphorylated at sites such as T181, T231, and S396 may initiate early pathological changes in tau by disrupting proper tau localization, initiating tau oligomerization, and facilitating tau accumulation and extracellular export. Thus, this review elucidates potential mechanisms through which tau post-translational modifications (PTMs) may simultaneously serve as key modulators of the spatial progression observed in AD development and as key instigators of early pathology related to neurodegeneration-relevant cellular dysfunctions. Full article

(This article belongs to the Special Issue Selective Vulnerability in Neurodegenerative Diseases)

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