RESUMO
Missense mutations in ubiquilin 2 (UBQLN2) cause ALS with frontotemporal dementia (ALS-FTD). Animal models of ALS are useful for understanding the mechanisms of pathogenesis and for preclinical investigations. However, previous rodent models carrying UBQLN2 mutations failed to manifest any sign of motor neuron disease. Here, we show that lines of mice expressing either the ALS-FTD-linked P497S or P506T UBQLN2 mutations have cognitive deficits, shortened lifespans, and develop motor neuron disease, mimicking the human disease. Neuropathologic analysis of the mice with end-stage disease revealed the accumulation of ubiquitinated inclusions in the brain and spinal cord, astrocytosis, a reduction in the number of hippocampal neurons, and reduced staining of TAR-DNA binding protein 43 in the nucleus, with concomitant formation of ubiquitin+ inclusions in the cytoplasm of spinal motor neurons. Moreover, both lines displayed denervation muscle atrophy and age-dependent loss of motor neurons that correlated with a reduction in the number of large-caliber axons. By contrast, two mouse lines expressing WT UBQLN2 were mostly devoid of clinical and pathological signs of disease. These UBQLN2 mouse models provide valuable tools for identifying the mechanisms underlying ALS-FTD pathogenesis and for investigating therapeutic strategies to halt disease.
Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Esclerose Lateral Amiotrófica/genética , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Demência Frontotemporal/genética , Mutação de Sentido Incorreto , Proteínas Adaptadoras de Transdução de Sinal , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/metabolismo , Animais , Proteínas Relacionadas à Autofagia , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Demência Frontotemporal/etiologia , Demência Frontotemporal/metabolismo , Humanos , Corpos de Inclusão/metabolismo , Camundongos , Neurônios Motores/metabolismo , UbiquitinaçãoRESUMO
Several recent breakthroughs have provided notable insights into the pathogenesis of amyotrophic lateral sclerosis (ALS), with some even shifting our thinking about this neurodegenerative disease and raising the question as to whether this disorder is a proteinopathy, a ribonucleopathy or both. In addition, these breakthroughs have revealed mechanistic links between ALS and frontotemporal dementia, as well as between ALS and other neurodegenerative diseases, such as the cerebellar atrophies, myotonic dystrophy and inclusion body myositis. Here, we summarize the new findings in ALS research, discuss what they have taught us about this disease and examine issues that are still outstanding.
Assuntos
Esclerose Lateral Amiotrófica/etiologia , Mutação/genética , Proteínas de Ligação a RNA/genética , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/genética , Animais , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/genética , HumanosRESUMO
The brain-spliced isoform of Myosin Va (BR-MyoVa) plays an important role in the transport of dense core secretory granules (SGs) to the plasma membrane in hormone and neuropeptide-producing cells. The molecular composition of the protein complex that recruits BR-MyoVa to SGs and regulates its function has not been identified to date. We have identified interaction between SG-associated proteins granuphilin-a/b (Gran-a/b), BR-MyoVa and Rab27a, a member of the Rab family of GTPases. Gran-a/b-BR-MyoVa interaction is direct, involves regions downstream of the Rab27-binding domain, and the C-terminal part of Gran-a determines exon specificity. MyoVa and Gran-a/b are partially colocalised on SGs and disruption of Gran-a/b-BR-MyoVa binding results in a perinuclear accumulation of SGs which augments nutrient-stimulated hormone secretion in pancreatic beta-cells. These results indicate the existence of at least another binding partner of BR-MyoVa that was identified as rabphilin-3A (Rph-3A). BR-MyoVa-Rph-3A interaction is also direct and enhanced when secretion is activated. The BR-MyoVa-Rph-3A and BR-MyoVa-Gran-a/b complexes are linked to a different subset of SGs, and simultaneous inhibition of these complexes nearly completely blocks stimulated hormone release. This study demonstrates that multiple binding partners of BR-MyoVa regulate SG transport, and this molecular mechanism is universally used by neuronal, endocrine and neuroendocrine cells.
Assuntos
Membrana Celular/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Miosina Tipo V/metabolismo , Vesículas Secretórias/metabolismo , Animais , Encéfalo/metabolismo , Hormônios/metabolismo , Células Secretoras de Insulina/metabolismo , Insulinoma/metabolismo , Insulinoma/patologia , Cadeias Pesadas de Miosina/genética , Miosina Tipo V/genética , Células PC12 , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Ligação Proteica , Isoformas de Proteínas , Transporte Proteico , Ratos , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab27 de Ligação ao GTPRESUMO
The discovery of the causative mutations and many of the predisposing risk factors for neurodegenerative disorders such as Amyotrophic Lateral Sclerosis, Alzheimer's, Parkinson's, and Huntington's disease (HD), has led to the development of a large number of genetic animal models of disease. In the case of HD, for example, over 20 different transgenic rodent models have been generated. These models have been of immense value in providing novel insights into mechanisms of disease, with the promise of accelerating the development of therapies that can delay the onset or slow the progression of the disease. Yet, despite extensive use of such models, no effective treatment for HD has been developed. Here, we discuss the value of animal models, highlighting their strengths and shortcomings in the context of translational research for HD.
Assuntos
Modelos Animais de Doenças , Doença de Huntington/terapia , Pesquisa Translacional Biomédica/métodos , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Doença de Huntington/genéticaRESUMO
Oligodendrocytes are well known targets for immune-mediated and infectious diseases, and have been suggested to play a role in neurodegeneration. Here, we report the involvement of oligodendrocytes and their progenitor cells in the ventral grey matter of the spinal cord in amyotrophic lateral sclerosis, a neurodegenerative disease of motor neurons. Degenerative changes in oligodendrocytes were abundantly present in human patients with amyotrophic lateral sclerosis and in an amyotrophic lateral sclerosis mouse model. In the mouse model, morphological changes in grey matter oligodendrocytes became apparent before disease onset, increasingly so during disease progression, and oligodendrocytes ultimately died. This loss was compensated by increased proliferation and differentiation of oligodendrocyte precursor cells. However, these newly differentiated oligodendrocytes were dysfunctional as suggested by their reduced myelin basic protein and monocarboxylate transporter 1 expression. Mutant superoxide dismutase 1 was found to directly affect monocarboxylate transporter 1 protein expression. Our data suggest that oligodendroglial dysfunction may be a contributor to motor neuron degeneration in amyotrophic lateral sclerosis.
Assuntos
Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/fisiopatologia , Modelos Animais de Doenças , Oligodendroglia/patologia , Esclerose Lateral Amiotrófica/enzimologia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Genes Reporter , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Oligodendroglia/enzimologia , Superóxido Dismutase/genéticaRESUMO
Iflavirus is a group of viruses distributed mainly in arthropod species. We surveyed Tribolium castaneum iflavirus (TcIV) in different laboratory strains and in Sequence Read Archives (SRA) in GenBank. TcIV is highly specific to only T. castaneum and is not found in seven other Tenebrionid species, including the closely related species T. freemani. The same strains from different laboratories and different strains displayed largely different degrees of infections in the examination of 50 different lines by using Taqman-based quantitative PCR. We found that ~63% (27 out of 43 strains) of T. castaneum strains in different laboratories are positive for TcIV PCR with large degrees of variation, in the range of seven orders of magnitude, indicating that the TcIV is highly fluctuating depending on the rearing conditions. The TcIV was prevalent in the nervous system with low levels found in the gonad and gut. The transovarial transmission was supported in the experiment with surface-sterilized eggs. Interestingly, TcIV infection did not show observable pathogenicity. TcIV offers an opportunity to study the interaction between the virus and the immune system of this model beetle species.
RESUMO
Oligodendrocytes (OLs) are important for myelination and shuttling energy metabolites lactate and pyruvate toward axons through their expression of monocarboxylate transporter 1 (MCT1). Recent studies suggest that loss of OL MCT1 causes axonal degeneration. However, it is unknown how widespread and chronic loss of MCT1 in OLs specifically affects neuronal energy homeostasis with aging. To answer this, MCT1 conditional null mice were generated that allow for OL-specific MCT1 ablation. We observe that MCT1 loss from OL lineage cells is dispensable for normal myelination and axonal energy homeostasis early in life. By contrast, loss of OL lineage MCT1 expression with aging leads to significant axonal degeneration with concomitant hypomyelination. These data support the hypothesis that MCT1 is important for neuronal energy homeostasis in the aging central nervous system (CNS). The reduction in OL MCT1 that occurs with aging may enhance the risk for axonal degeneration and atrophy in neurodegenerative diseases.
Assuntos
Axônios/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Bainha de Mielina/metabolismo , Degeneração Neural/metabolismo , Oligodendroglia/metabolismo , Simportadores/metabolismo , Animais , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Transportadores de Ácidos Monocarboxílicos/deficiência , Bainha de Mielina/patologia , Oligodendroglia/patologia , Simportadores/deficiênciaRESUMO
BACKGROUND: Alcohol dependence is a significant issue contributing to disease burden. Changes in cortisol concentrations during alcohol withdrawal are associated with cognitive deficits and symptoms of depression. Current treatments are only successful for a small proportion of people and do not target cognitive deficits and symptoms of depression experienced by those who are alcohol dependent. The aim of this research is to determine the potential efficacy of mifepristone, a type II glucocorticoid receptor antagonist, to prevent symptoms of depression and cognitive deficits following alcohol detoxification. METHODS: This was a phase 2 therapeutic use trial. It was a double-blind randomised controlled clinical trial of mifepristone versus inactive placebo treatment. The trial aimed to recruit 120 participants who met the inclusion criteria: (1) male, (2) aged 18-60 years inclusive, and (3) alcohol dependent for 5 or more years. Participants were randomised to 600 mg a day mifepristone (200 mg morning, afternoon, and evening) for 7 days and 400 mg for the subsequent 7 days (200 mg morning and evening) or the equivalent number of placebo tablets for 14 days. Primary outcome measures were cognitive function (measured using the Cambridge Neuropsychological Test Automated Battery (CANTAB)) and symptoms of depression (measured using the Beck Depression Inventory (BDI)) at 4 weeks post-randomisation. RESULTS: Difficulties recruiting participants due to significant changes in the provision of inpatient care for alcohol dependence resulted in only 27 participants recruited to the trial, with data available for 21 participants. Fourteen participants were randomised to receive mifepristone and 13 to receive placebo. CONCLUSION: Larger trials would be needed to draw conclusions about the efficacy of mifepristone. TRIAL REGISTRATION: ISRCTN registry ISRCTN54001953 . Registered on 29 September 2011.
Assuntos
Alcoolismo , Alcoolismo/diagnóstico , Alcoolismo/tratamento farmacológico , Cognição , Depressão/diagnóstico , Depressão/tratamento farmacológico , Método Duplo-Cego , Humanos , Masculino , Mifepristona/efeitos adversos , Resultado do TratamentoRESUMO
The Cre-loxP system is invaluable for spatial and temporal control of gene knockout, knockin, and reporter expression in the mouse nervous system. However, we report varying probabilities of unexpected germline recombination in distinct Cre driver lines designed for nervous system-specific recombination. Selective maternal or paternal germline recombination is showcased with sample Cre lines. Collated data reveal germline recombination in over half of 64 commonly used Cre driver lines, in most cases with a parental sex bias related to Cre expression in sperm or oocytes. Slight differences among Cre driver lines utilizing common transcriptional control elements affect germline recombination rates. Specific target loci demonstrated differential recombination; thus, reporters are not reliable proxies for another locus of interest. Similar principles apply to other recombinase systems and other genetically targeted organisms. We hereby draw attention to the prevalence of germline recombination and provide guidelines to inform future research for the neuroscience and broader molecular genetics communities.
Assuntos
Marcação de Genes/métodos , Integrases/genética , Neurônios/metabolismo , Oócitos/metabolismo , Recombinação Genética/genética , Espermatozoides/metabolismo , Animais , Feminino , Genes Reporter , Células Germinativas , Masculino , Camundongos , Camundongos Transgênicos , MosaicismoRESUMO
Microglial activation is a hallmark of all neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Here, a detailed characterization of the microglial cell population within the spinal cord of a mouse model of familial ALS was performed. Using flow cytometry, we detected three distinct microglial populations within the spinal cord of mice overexpressing mutant superoxide dismutase (SOD1): mature microglial cells (CD11b(+), CD45(low)), myeloid precursor cells (CD11b(+), CD45(int)), and macrophages (CD11b(+), CD45(high)). Characterization of cell proliferation within the CNS of SOD1(G93A) mice revealed that the expansion in microglial cell population is mainly attributable to the proliferation of myeloid precursor cells. To assess the contribution of proliferating microglia in motor neuron degeneration, we generated CD11b-TK(mut-30); SOD1(G93A) doubly transgenic mice that allow the elimination of proliferating microglia on administration of ganciclovir. Surprisingly, a 50% reduction in reactive microglia specifically in the lumbar spinal cord of CD11b-TK(mut-30); SOD1(G93A) doubly transgenic mice had no effect on motor neuron degeneration. This suggests that proliferating microglia-expressing mutant SOD1 are not central contributors of the neurodegenerative process in ALS caused by mutant SOD1.
Assuntos
Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Microglia/patologia , Neurônios Motores/patologia , Mutação , Degeneração Neural/patologia , Superóxido Dismutase/genética , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/fisiopatologia , Animais , Biomarcadores/metabolismo , Antígeno CD11b/metabolismo , Contagem de Células , Proliferação de Células , Senescência Celular , Células Dendríticas/metabolismo , Progressão da Doença , Camundongos , Camundongos Transgênicos , Microglia/imunologia , Degeneração Neural/etiologia , Neuroglia/patologia , Fenótipo , Medula Espinal/patologia , Células-Tronco/patologia , Superóxido Dismutase-1 , Linfócitos T/patologiaRESUMO
Despite expanding knowledge regarding the role of astroglia in regulating neuronal function, little is known about regional or functional subgroups of brain astroglia and how they may interact with neurons. We use an astroglia-specific promoter fragment in transgenic mice to identify an anatomically defined subset of adult gray matter astroglia. Using transcriptomic and histological analyses, we generate a combinatorial profile for the in vivo identification and characterization of this astroglia subpopulation. These astroglia are enriched in mouse cortical layer V; express distinct molecular markers, including Norrin and leucine-rich repeat-containing G-protein-coupled receptor 6 (LGR6), with corresponding layer-specific neuronal ligands; are found in the human cortex; and modulate neuronal activity. Astrocytic Norrin appears to regulate dendrites and spines; its loss, as occurring in Norrie disease, contributes to cortical dendritic spine loss. These studies provide evidence that human and rodent astroglia subtypes are regionally and functionally distinct, can regulate local neuronal dendrite and synaptic spine development, and contribute to disease.
Assuntos
Astrócitos/metabolismo , Córtex Cerebral/metabolismo , Proteínas do Olho/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Animais , Células Cultivadas , Espinhas Dendríticas/fisiologia , Substância Cinzenta/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Córtex Motor/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , TranscriptomaRESUMO
Oligodendrocytes are glial cells that populate the entire CNS after they have differentiated from oligodendrocyte progenitor cells. From birth onward, oligodendrocytes initiate wrapping of neuronal axons with a multilamellar lipid structure called myelin. Apart from their well-established function in action potential propagation, more recent data indicate that oligodendrocytes are essential for providing metabolic support to neurons. Oligodendrocytes transfer energy metabolites to neurons through cytoplasmic "myelinic" channels and monocarboxylate transporters, which allow for the fast delivery of short-carbon-chain energy metabolites like pyruvate and lactate to neurons. These substrates are metabolized and contribute to ATP synthesis in neurons. This Review will discuss our current understanding of this metabolic supportive function of oligodendrocytes and its potential impact in human neurodegenerative disease and related animal models.
Assuntos
Axônios/metabolismo , Bainha de Mielina/metabolismo , Neurônios/citologia , Oligodendroglia/citologia , Trifosfato de Adenosina/metabolismo , Esclerose Lateral Amiotrófica/metabolismo , Animais , Diferenciação Celular , Conexinas/metabolismo , Junções Comunicantes/metabolismo , Humanos , Camundongos , Esclerose Múltipla/metabolismo , Neuroglia/citologia , Neuroglia/metabolismo , Neurônios/metabolismo , Oligodendroglia/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais , Células-Tronco/citologia , Células-Tronco/metabolismoRESUMO
Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease affecting upper and lower motor neurons in the central nervous system. Patients with ALS develop extensive muscle wasting and atrophy leading to paralysis and death 3 to 5 years after disease onset. The condition may be familial (fALS 10%) or sporadic ALS (sALS, 90%). The large majority of fALS cases are due to genetic mutations in the Superoxide dismutase 1 gene (SOD1, 15% of fALS) and repeat nucleotide expansions in the gene encoding C9ORF72 (â¼ 40% to 50% of fALS and â¼ 10% of sALS). Studies suggest that ALS is mediated through aberrant protein homeostasis (i.e., ER stress and autophagy) and/or changes in RNA processing (as in all non-SOD1-mediated ALS). In all of these cases, animal models suggest that the disorder is mediated non-cell autonomously, i.e., not only motor neurons are involved, but glial cells including microglia, astrocytes, and oligodendrocytes, and other neuronal subpopulations are also implicated in the pathogenesis. Provided in this unit is a review of ALS rodent models, including discussion of their relative advantages and disadvantages. Emphasis is placed on correlating the model phenotype with the human condition and the utility of the model for defining the disease process. Information is also presented on RNA processing studies in ALS research, with particular emphasis on the newest ALS rodent models.
Assuntos
Esclerose Lateral Amiotrófica/fisiopatologia , Sistema Nervoso Central/fisiopatologia , Modelos Animais de Doenças , Neurônios Motores/metabolismo , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Animais , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/enzimologia , Proteínas de Ligação a DNA/agonistas , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Camundongos , Camundongos Knockout , Camundongos Mutantes Neurológicos , Camundongos Transgênicos , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/enzimologia , Mutação , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Regiões Promotoras Genéticas/efeitos dos fármacos , Processamento Pós-Transcricional do RNA/efeitos dos fármacos , Ratos , Ratos Mutantes , Ratos Transgênicos , Superóxido Dismutase/química , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1RESUMO
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Disease onset and progression are variable, with survival ranging from months to decades. Factors underlying this variability may represent targets for therapeutic intervention. Here, we have screened a zebrafish model of ALS and identified Epha4, a receptor in the ephrin axonal repellent system, as a modifier of the disease phenotype in fish, rodents and humans. Genetic as well as pharmacological inhibition of Epha4 signaling rescues the mutant SOD1 phenotype in zebrafish and increases survival in mouse and rat models of ALS. Motor neurons that are most vulnerable to degeneration in ALS express higher levels of Epha4, and neuromuscular re-innervation by axotomized motor neurons is inhibited by the presence of Epha4. In humans with ALS, EPHA4 expression inversely correlates with disease onset and survival, and loss-of-function mutations in EPHA4 are associated with long survival. Furthermore, we found that knockdown of Epha4 also rescues the axonopathy induced by expression of mutant TAR DNA-binding protein 43 (TDP-43), another protein causing familial ALS, and the axonopathy induced by knockdown of survival of motor neuron 1, a model for spinomuscular atrophy. This suggests that Epha4 generically modulates the vulnerability of (motor) neurons to axonal degeneration and may represent a new target for therapeutic intervention.
Assuntos
Esclerose Lateral Amiotrófica/fisiopatologia , Neurônios Motores/patologia , Fenótipo , Receptor EphA4/metabolismo , Transdução de Sinais/fisiologia , Superóxido Dismutase/metabolismo , Esclerose Lateral Amiotrófica/metabolismo , Análise de Variância , Animais , Sequência de Bases , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Morfolinos/genética , Neurônios Motores/metabolismo , Ratos , Teste de Desempenho do Rota-Rod , Análise de Sequência de DNA , Estatísticas não Paramétricas , Superóxido Dismutase-1 , Peixe-ZebraRESUMO
Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) are characterised by the appearance of reactive microglial and astroglial cells, a process referred to as neuroinflammation. In transgenic mouse models of mutant SOD1-associated familial ALS, reactive microglial cells and astrocytes actively contribute to the death of motor neurons. The biological processes that drive this glial reaction are complex and have both beneficial and deleterious effects on motor neurons. Therapeutic interventions targeting these cells are being explored. An improved understanding of the biological processes that cause neuroinflammation will help to define its medical importance and to identify the therapeutic potential of interfering with this reaction.
Assuntos
Esclerose Lateral Amiotrófica/imunologia , Esclerose Lateral Amiotrófica/metabolismo , Neuroglia/imunologia , Neuroglia/metabolismo , Animais , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Doença dos Neurônios Motores/imunologia , Doença dos Neurônios Motores/metabolismo , Transdução de Sinais/fisiologia , Linfócitos T/fisiologiaRESUMO
Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are overlapping neurodegenerative disorders. Mutations in the growth factor progranulin (PGRN) gene cause FTLD, sometimes in conjunction with ALS; such mutations are also observed in some ALS patients. Most PGRN mutations underlying FTLD are null mutations that result in reduced PGRN levels. We investigated PGRN expression in human ALS and in mouse models of motor neuron degeneration. Progranulin plasma or CSF levels in newly diagnosed ALS patients did not differ from those in healthy or disease controls (PGRN mutation-negative FTLD and Alzheimer disease patients). In the mutant SOD1 mouse model of ALS, spinal cord PGRN levels were normal in presymptomatic animals but increased during the degenerative process. This increase in PGRN correlated with enhanced expression of PGRN in microglia. In CSF, PGRN levels were normal in presymptomatic and early symptomatic animals, but with disease progression, a raise in PGRN was detectable. These data indicate that upregulation of PGRN is a marker of the microglial response that occurs with progression in motor neuron diseases.