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1.
RNA ; 28(1): 97-113, 2022 01.
Article in English | MEDLINE | ID: mdl-34706979

ABSTRACT

The genetics of human disease serves as a robust and unbiased source of insight into human biology, both revealing fundamental cellular processes and exposing the vulnerabilities associated with their dysfunction. Over the last decade, the genetics of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have epitomized this concept, as studies of ALS-FTD-causing mutations have yielded fundamental discoveries regarding the role of biomolecular condensation in organizing cellular contents while implicating disturbances in condensate dynamics as central drivers of neurodegeneration. Here we review this genetic evidence, highlight its intersection with patient pathology, and discuss how studies in model systems have revealed a role for aberrant condensation in neuronal dysfunction and death. We detail how multiple, distinct types of disease-causing mutations promote pathological phase transitions that disturb the dynamics and function of ribonucleoprotein (RNP) granules. Dysfunction of RNP granules causes pleiotropic defects in RNA metabolism and can drive the evolution of these structures to end-stage pathological inclusions characteristic of ALS-FTD. We propose that aberrant phase transitions of these complex condensates in cells provide a parsimonious explanation for the widespread cellular abnormalities observed in ALS as well as certain histopathological features that characterize late-stage disease.


Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Biomolecular Condensates/chemistry , Cytoplasmic Ribonucleoprotein Granules/chemistry , Frontotemporal Dementia/genetics , RNA-Binding Proteins/chemistry , RNA/chemistry , Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/pathology , Binding Sites , Biomolecular Condensates/metabolism , Cell Death/genetics , Cytoplasmic Ribonucleoprotein Granules/genetics , Cytoplasmic Ribonucleoprotein Granules/metabolism , Frontotemporal Dementia/metabolism , Frontotemporal Dementia/pathology , Humans , Molecular Dynamics Simulation , Mutation , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Neurons/pathology , Phase Transition , Protein Binding , RNA/genetics , RNA/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Ribonucleoproteins/chemistry , Ribonucleoproteins/genetics , Ribonucleoproteins/metabolism
2.
Nat Rev Neurol ; 15(5): 272-286, 2019 May.
Article in English | MEDLINE | ID: mdl-30890779

ABSTRACT

Biomolecular condensation arising through phase transitions has emerged as an essential organizational strategy that governs many aspects of cell biology. In particular, the role of phase transitions in the assembly of large, complex ribonucleoprotein (RNP) granules has become appreciated as an important regulator of RNA metabolism. In parallel, genetic, histopathological and cell and molecular studies have provided evidence that disturbance of phase transitions is an important driver of neurological diseases, notably amyotrophic lateral sclerosis (ALS), but most likely also other diseases. Indeed, our growing knowledge of the biophysics underlying biological phase transitions suggests that this process offers a unifying mechanism to explain the numerous and diverse disturbances in RNA metabolism that have been observed in ALS and some related diseases - specifically, that these diseases are driven by disturbances in the material properties of RNP granules. Here, we review the evidence for this hypothesis, emphasizing the reciprocal roles in which disease-related protein and disease-related RNA can lead to disturbances in the material properties of RNP granules and consequent pathogenesis. Additionally, we review evidence that implicates aberrant phase transitions as a contributing factor to a larger set of neurodegenerative diseases, including frontotemporal dementia, certain repeat expansion diseases and Alzheimer disease.


Subject(s)
Brain/metabolism , Neurodegenerative Diseases/metabolism , Biophysics , Humans , Phase Transition , Ribonucleoproteins/metabolism
3.
Immunity ; 43(4): 715-26, 2015 Oct 20.
Article in English | MEDLINE | ID: mdl-26488816

ABSTRACT

CARD9 is a central component of anti-fungal innate immune signaling via C-type lectin receptors, and several immune-related disorders are associated with CARD9 alterations. Here, we used a rare CARD9 variant that confers protection against inflammatory bowel disease as an entry point to investigating CARD9 regulation. We showed that the protective variant of CARD9, which is C-terminally truncated, acted in a dominant-negative manner for CARD9-mediated cytokine production, indicating an important role for the C terminus in CARD9 signaling. We identified TRIM62 as a CARD9 binding partner and showed that TRIM62 facilitated K27-linked poly-ubiquitination of CARD9. We identified K125 as the ubiquitinated residue on CARD9 and demonstrated that this ubiquitination was essential for CARD9 activity. Furthermore, we showed that similar to Card9-deficient mice, Trim62-deficient mice had increased susceptibility to fungal infection. In this study, we utilized a rare protective allele to uncover a TRIM62-mediated mechanism for regulation of CARD9 activation.


Subject(s)
CARD Signaling Adaptor Proteins/physiology , Candidiasis, Invasive/immunology , Receptors, Angiotensin/physiology , Receptors, Endothelin/physiology , Ubiquitin-Protein Ligases/physiology , Adjuvants, Immunologic/pharmacology , Animals , CARD Signaling Adaptor Proteins/chemistry , CARD Signaling Adaptor Proteins/deficiency , CARD Signaling Adaptor Proteins/genetics , Candidiasis, Invasive/genetics , Colitis/chemically induced , Colitis/genetics , Colitis/prevention & control , Cytokines/biosynthesis , Dendritic Cells/immunology , Dendritic Cells/metabolism , Genes, Dominant , Genetic Predisposition to Disease , HEK293 Cells , HeLa Cells , Humans , Inflammatory Bowel Diseases/genetics , Mice , Mice, 129 Strain , Mice, Knockout , Protein Interaction Mapping , Protein Isoforms/chemistry , Protein Isoforms/genetics , Protein Isoforms/physiology , Protein Processing, Post-Translational , Protein Structure, Tertiary , Receptors, Angiotensin/chemistry , Receptors, Angiotensin/deficiency , Receptors, Endothelin/chemistry , Receptors, Endothelin/deficiency , Recombinant Fusion Proteins/metabolism , Signal Transduction , Specific Pathogen-Free Organisms , Tripartite Motif Proteins , Ubiquitin-Protein Ligases/chemistry , Ubiquitination
4.
J Virol ; 86(15): 7988-8001, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22623766

ABSTRACT

La Crosse virus (LACV) is a leading cause of pediatric encephalitis and aseptic meningitis in the midwestern and southern United States, where it is considered an emerging human pathogen. No specific therapies or vaccines are available for LACV or any other orthobunyaviruses. Inhibition of LACV entry into cells is a potential target for therapeutic intervention, but this approach is limited by our current knowledge of the entry process. Here, we determined that clathrin-mediated endocytosis is the primary mechanism of orthobunyavirus entry and identified key cellular factors in this process. First, we demonstrated that LACV colocalized with clathrin shortly after infection in HeLa cells; we then confirmed the functional requirement of dynamin- and clathrin-mediated endocytosis for orthobunyavirus entry using several independent assays and, importantly, extended these findings to primary neuronal cultures. We also determined that macropinocytosis and caveolar endocytosis, both established routes of virus entry, are not critical for cellular entry of LACV. Moreover, we demonstrated that LACV infection is dependent on Rab5, which plays an important regulatory role in early endosomes, but not on Rab7, which is associated with late endosomes. These findings provide the first description of bunyavirus entry into cells of the central nervous system, where infection can cause severe neurological disease, and will aid in the design and development of antivirals and therapeutics that may be useful in the treatment of LACV and, more broadly, arboviral infections of the central nervous system.


Subject(s)
Clathrin/metabolism , Encephalitis, California/metabolism , Endocytosis , Endosomes/metabolism , La Crosse virus/metabolism , Virus Internalization , Animals , Chlorocebus aethiops , Clathrin/genetics , Cricetinae , Encephalitis, California/drug therapy , Encephalitis, California/genetics , Endosomes/genetics , Endosomes/virology , HeLa Cells , Humans , La Crosse virus/genetics , Vero Cells , rab GTP-Binding Proteins/genetics , rab GTP-Binding Proteins/metabolism , rab5 GTP-Binding Proteins/genetics , rab5 GTP-Binding Proteins/metabolism , rab7 GTP-Binding Proteins
5.
Neuron ; 67(6): 936-52, 2010 Sep 23.
Article in English | MEDLINE | ID: mdl-20869592

ABSTRACT

Spinobulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by expansion of a polyglutamine tract in the androgen receptor (AR). This mutation confers toxic function to AR through unknown mechanisms. Mutant AR toxicity requires binding of its hormone ligand, suggesting that pathogenesis involves ligand-induced changes in AR. However, whether toxicity is mediated by native AR function or a novel AR function is unknown. We systematically investigated events downstream of ligand-dependent AR activation in a Drosophila model of SBMA. We show that nuclear translocation of AR is necessary, but not sufficient, for toxicity and that DNA binding by AR is necessary for toxicity. Mutagenesis studies demonstrated that a functional AF-2 domain is essential for toxicity, a finding corroborated by a genetic screen that identified AF-2 interactors as dominant modifiers of degeneration. These findings indicate that SBMA pathogenesis is mediated by misappropriation of native protein function, a mechanism that may apply broadly to polyglutamine diseases.


Subject(s)
Muscular Disorders, Atrophic/etiology , Muscular Disorders, Atrophic/genetics , Mutation/genetics , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Actins/metabolism , Animals , Animals, Genetically Modified , Blindness/genetics , Blindness/pathology , Cell Line, Transformed , Disease Models, Animal , Drosophila , Drosophila Proteins/genetics , Eye/metabolism , Eye/pathology , Female , Furylfuramide/metabolism , Gene Expression Profiling/methods , Gene Expression Regulation/genetics , Humans , Larva/physiology , Locomotion/genetics , Motor Neurons/metabolism , Muscular Disorders, Atrophic/pathology , Mutagenesis/physiology , Neuromuscular Junction/pathology , Oligonucleotide Array Sequence Analysis/methods , Phenotype , Principal Component Analysis , Protein Transport/genetics , RNA Interference/physiology , Receptors, Androgen/chemistry , Salivary Glands/metabolism , Salivary Glands/pathology , Statistics, Nonparametric , Transfection/methods , Trinucleotide Repeat Expansion , Tubulin/metabolism
6.
J Neurosci Res ; 88(10): 2207-16, 2010 Aug 01.
Article in English | MEDLINE | ID: mdl-20336775

ABSTRACT

Expanded polyglutamine tracts cause neurodegeneration through a toxic gain-of-function mechanism. Generation of inclusions is a common feature of polyglutamine diseases and other protein misfolding disorders. Inclusion formation is likely to be a defensive response of the cell to the presence of unfolded protein. Recently, the compound B2 has been shown to increase inclusion formation and decrease toxicity of polyglutamine-expanded huntingtin in cultured cells. We explored the effect of B2 on spinal and bulbar muscular atrophy (SBMA). SBMA is caused by expansion of polyglutamine in the androgen receptor (AR) and is characterized by the loss of motor neurons in the brainstem and spinal cord. We found that B2 increases the deposition of mutant AR into nuclear inclusions, without altering the ligand-induced aggregation, expression, or subcellular distribution of the mutant protein. The effect of B2 on inclusions was associated with a decrease in AR transactivation function. We show that B2 reduces mutant AR toxicity in cell and fly models of SBMA, further supporting the idea that accumulation of polyglutamine-expanded protein into inclusions is protective. Our findings suggest B2 as a novel approach to therapy for SBMA.


Subject(s)
Bulbo-Spinal Atrophy, X-Linked/drug therapy , Bulbo-Spinal Atrophy, X-Linked/metabolism , Neuroprotective Agents/pharmacology , Nitroquinolines/pharmacology , Peptides/metabolism , Piperazines/pharmacology , Receptors, Androgen/metabolism , Animals , Animals, Genetically Modified , Cell Line , Disease Models, Animal , Drosophila melanogaster , Humans , Intracellular Space/drug effects , Intracellular Space/metabolism , Intranuclear Inclusion Bodies/drug effects , Intranuclear Inclusion Bodies/metabolism , Ligands , Mutation , Protein Multimerization , Rats , Receptors, Androgen/genetics
7.
Biochim Biophys Acta ; 1782(12): 691-9, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18930136

ABSTRACT

Protein degradation is an essential cellular function that, when dysregulated or impaired, can lead to a wide variety of disease states. The two major intracellular protein degradation systems are the ubiquitin-proteasome system (UPS) and autophagy, a catabolic process that involves delivery of cellular components to the lysosome for degradation. While the UPS has garnered much attention as it relates to neurodegenerative disease, important links between autophagy and neurodegeneration have also become evident. Furthermore, recent studies have revealed interaction between the UPS and autophagy, suggesting a coordinated and complementary relationship between these degradation systems that becomes critical in times of cellular stress. Here we describe autophagy and review evidence implicating this system as an important player in the pathogenesis of neurodegenerative disease. We discuss the role of autophagy in neurodegeneration and review its neuroprotective functions as revealed by experimental manipulation in disease models. Finally, we explore potential parallels and connections between autophagy and the UPS, highlighting their collaborative roles in protecting against neurodegenerative disease.


Subject(s)
Autophagy/physiology , Neurodegenerative Diseases/physiopathology , Neuroprotective Agents/therapeutic use , Proteasome Endopeptidase Complex/metabolism , Ubiquitin/metabolism , Animals , Humans , Neurodegenerative Diseases/therapy
8.
Nature ; 447(7146): 859-63, 2007 Jun 14.
Article in English | MEDLINE | ID: mdl-17568747

ABSTRACT

A prominent feature of late-onset neurodegenerative diseases is accumulation of misfolded protein in vulnerable neurons. When levels of misfolded protein overwhelm degradative pathways, the result is cellular toxicity and neurodegeneration. Cellular mechanisms for degrading misfolded protein include the ubiquitin-proteasome system (UPS), the main non-lysosomal degradative pathway for ubiquitinated proteins, and autophagy, a lysosome-mediated degradative pathway. The UPS and autophagy have long been viewed as complementary degradation systems with no point of intersection. This view has been challenged by two observations suggesting an apparent interaction: impairment of the UPS induces autophagy in vitro, and conditional knockout of autophagy in the mouse brain leads to neurodegeneration with ubiquitin-positive pathology. It is not known whether autophagy is strictly a parallel degradation system, or whether it is a compensatory degradation system when the UPS is impaired; furthermore, if there is a compensatory interaction between these systems, the molecular link is not known. Here we show that autophagy acts as a compensatory degradation system when the UPS is impaired in Drosophila melanogaster, and that histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase that interacts with polyubiquitinated proteins, is an essential mechanistic link in this compensatory interaction. We found that compensatory autophagy was induced in response to mutations affecting the proteasome and in response to UPS impairment in a fly model of the neurodegenerative disease spinobulbar muscular atrophy. Autophagy compensated for impaired UPS function in an HDAC6-dependent manner. Furthermore, expression of HDAC6 was sufficient to rescue degeneration associated with UPS dysfunction in vivo in an autophagy-dependent manner. This study suggests that impairment of autophagy (for example, associated with ageing or genetic variation) might predispose to neurodegeneration. Morover, these findings suggest that it may be possible to intervene in neurodegeneration by augmenting HDAC6 to enhance autophagy.


Subject(s)
Autophagy/physiology , Drosophila Proteins/metabolism , Drosophila melanogaster/metabolism , Histone Deacetylases/metabolism , Neurodegenerative Diseases/metabolism , Proteasome Endopeptidase Complex/metabolism , Ubiquitin/metabolism , Animals , Autophagy/genetics , Disease Models, Animal , Drosophila melanogaster/genetics , Histone Deacetylase 6 , Humans , Muscular Disorders, Atrophic/genetics , Muscular Disorders, Atrophic/metabolism , Neurodegenerative Diseases/genetics , Peptides/genetics , Peptides/metabolism , Proteasome Endopeptidase Complex/genetics , Receptors, Androgen/genetics , Receptors, Androgen/metabolism
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