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1.
Nat Commun ; 11(1): 5781, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33188183

RESUMO

The temporal molecular changes that lead to disease onset and progression in Alzheimer's disease (AD) are still unknown. Here we develop a temporal model for these unobserved molecular changes with a manifold learning method applied to RNA-Seq data collected from human postmortem brain samples collected within the ROS/MAP and Mayo Clinic RNA-Seq studies. We define an ordering across samples based on their similarity in gene expression and use this ordering to estimate the molecular disease stage-or disease pseudotime-for each sample. Disease pseudotime is strongly concordant with the burden of tau (Braak score, P = 1.0 × 10-5), Aß (CERAD score, P = 1.8 × 10-5), and cognitive diagnosis (P = 3.5 × 10-7) of late-onset (LO) AD. Early stage disease pseudotime samples are enriched for controls and show changes in basic cellular functions. Late stage disease pseudotime samples are enriched for late stage AD cases and show changes in neuroinflammation and amyloid pathologic processes. We also identify a set of late stage pseudotime samples that are controls and show changes in genes enriched for protein trafficking, splicing, regulation of apoptosis, and prevention of amyloid cleavage pathways. In summary, we present a method for ordering patients along a trajectory of LOAD disease progression from brain transcriptomic data.


Assuntos
Encéfalo/patologia , Degeneração Neural/patologia , Algoritmos , Doença de Alzheimer/patologia , Progressão da Doença , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Degeneração Neural/genética , Córtex Pré-Frontal/patologia , Fatores de Tempo , Aprendizado de Máquina não Supervisionado
2.
PLoS One ; 15(11): e0240911, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33211695

RESUMO

PURPOSE: The treatment strategy is different for acute traumatic peripheral nerve injury and acute compressive neuropathy. This study aimed to compare magnetic resonance imaging (MRI) features of acute traumatic peripheral nerve injury and acute compressive neuropathy in a rat model. MATERIALS AND METHODS: Twenty female Sprague-Dawley rats were divided into two groups. In the crush injury group (n = 10), the unilateral sciatic nerve was crushed using forceps to represent acute traumatic peripheral nerve injury. In the compression injury group (n = 10), the unilateral sciatic nerve was ligated using silk to represent acute compressive neuropathy. The MRI of eight rats from each group were acquired on postoperative days 3 and 10. Fat-suppressed T2-weighted images were acquired. Changes in the injured nerve were divided into three grades. A Fisher's exact test was used to compare the changes in the nerves of the two groups. Histological staining and a western blot analysis were performed on one rat in each group on day 3. Neurofilament, myelin basic protein (MBP), and p75NTR staining were performed. Expression of neurofilament, MBP, p75NTR, and c-jun was evaluated by western blot analysis. RESULTS: MR neurography revealed substantial nerve changes in the compression injury group compared with the crush injury group at two-time points (p = 0.001 on day 3, p = 0.026 on day 10). The histopathological analysis indicated the destruction of the axon and myelin, mainly at the injury site and the distal portion of the injury in the crush injury group. It was prominent in the proximal portion, the injury site, and the distal portion of the injury in the compression injury group. The degree of axonal and myelin destruction was more pronounced in the compression injury group than in the crush injury group. CONCLUSION: MR neurography showed prominent and long-segmental changes associated with the injured nerve in acute compressive neuropathy compared with acute traumatic peripheral nerve injury.


Assuntos
Síndromes de Compressão Nervosa/diagnóstico por imagem , Traumatismos dos Nervos Periféricos/diagnóstico por imagem , Doença Aguda , Animais , Lesões por Esmagamento/diagnóstico por imagem , Lesões por Esmagamento/metabolismo , Lesões por Esmagamento/patologia , Modelos Animais de Doenças , Feminino , Imagem por Ressonância Magnética/métodos , Síndromes de Compressão Nervosa/metabolismo , Síndromes de Compressão Nervosa/patologia , Degeneração Neural/diagnóstico por imagem , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Proteínas do Tecido Nervoso/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/patologia , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/lesões , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia
3.
PLoS Genet ; 16(10): e1009052, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33064774

RESUMO

Ciliary microtubules are subject to post-translational modifications that act as a "Tubulin Code" to regulate motor traffic, binding proteins and stability. In humans, loss of CCP1, a cytosolic carboxypeptidase and tubulin deglutamylating enzyme, causes infantile-onset neurodegeneration. In C. elegans, mutations in ccpp-1, the homolog of CCP1, result in progressive degeneration of neuronal cilia and loss of neuronal function. To identify genes that regulate microtubule glutamylation and ciliary integrity, we performed a forward genetic screen for suppressors of ciliary degeneration in ccpp-1 mutants. We isolated the ttll-5(my38) suppressor, a mutation in a tubulin tyrosine ligase-like glutamylase gene. We show that mutation in the ttll-4, ttll-5, or ttll-11 gene suppressed the hyperglutamylation-induced loss of ciliary dye filling and kinesin-2 mislocalization in ccpp-1 cilia. We also identified the nekl-4(my31) suppressor, an allele affecting the NIMA (Never in Mitosis A)-related kinase NEKL-4/NEK10. In humans, NEK10 mutation causes bronchiectasis, an airway and mucociliary transport disorder caused by defective motile cilia. C. elegans NEKL-4 localizes to the ciliary base but does not localize to cilia, suggesting an indirect role in ciliary processes. This work defines a pathway in which glutamylation, a component of the Tubulin Code, is written by TTLL-4, TTLL-5, and TTLL-11; is erased by CCPP-1; is read by ciliary kinesins; and its downstream effects are modulated by NEKL-4 activity. Identification of regulators of microtubule glutamylation in diverse cellular contexts is important to the development of effective therapies for disorders characterized by changes in microtubule glutamylation. By identifying C. elegans genes important for neuronal and ciliary stability, our work may inform research into the roles of the tubulin code in human ciliopathies and neurodegenerative diseases.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Carboxipeptidases/genética , Degeneração Neural/genética , Peptídeo Sintases/genética , Tubulina (Proteína)/genética , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Transporte/genética , Cílios/genética , Cílios/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Cinesina/genética , Microtúbulos/genética , Mutação/genética , Quinases Relacionadas a NIMA/genética , Degeneração Neural/patologia , Neurônios/metabolismo , Neurônios/patologia , Processamento de Proteína Pós-Traducional/genética
4.
PLoS Genet ; 16(10): e1008844, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33085661

RESUMO

Balanced mitochondrial fission and fusion play an important role in shaping and distributing mitochondria, as well as contributing to mitochondrial homeostasis and adaptation to stress. In particular, mitochondrial fission is required to facilitate degradation of damaged or dysfunctional units via mitophagy. Two Parkinson's disease factors, PINK1 and Parkin, are considered key mediators of damage-induced mitophagy, and promoting mitochondrial fission is sufficient to suppress the pathological phenotypes in Drosophila Pink1/parkin mutants. We sought additional factors that impinge on mitochondrial dynamics and which may also suppress Pink1/parkin phenotypes. We found that the Drosophila phosphatidylinositol 4-kinase IIIß homologue, Four wheel drive (Fwd), promotes mitochondrial fission downstream of the pro-fission factor Drp1. Previously described only as male sterile, we identified several new phenotypes in fwd mutants, including locomotor deficits and shortened lifespan, which are accompanied by mitochondrial dysfunction. Finally, we found that fwd overexpression can suppress locomotor deficits and mitochondrial disruption in Pink1/parkin mutants, consistent with its function in promoting mitochondrial fission. Together these results shed light on the complex mechanisms of mitochondrial fission and further underscore the potential of modulating mitochondrial fission/fusion dynamics in the context of neurodegeneration.


Assuntos
Proteínas do Citoesqueleto/genética , Proteínas de Drosophila/genética , Proteínas de Ligação ao GTP/genética , Doença de Parkinson/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Proteínas Serina-Treonina Quinases/genética , Ubiquitina-Proteína Ligases/genética , Animais , Modelos Animais de Doenças , Drosophila melanogaster/genética , Regulação da Expressão Gênica/genética , Humanos , Locomoção/genética , Mitocôndrias/genética , Mitocôndrias/patologia , Dinâmica Mitocondrial/genética , Mitofagia/genética , Proteínas Mutantes/genética , Degeneração Neural/genética , Degeneração Neural/patologia , Doença de Parkinson/patologia
5.
PLoS One ; 15(9): e0238637, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32903270

RESUMO

Neonicotinoids, a class of insecticides structurally similar to nicotine that target biting and sucking insects, are the most widely used insecticides today, in part due to their supposed low toxicity in other organisms. However, a growing body of research has found that even low doses of neonicotinoids can induce unexpected negative effects on the physiology and survival of a wide range of non-target organisms. Importantly, no work has been done on the commercial formulations of pesticides that include imidacloprid as the active ingredient, but that also contain many other components. The present study examines the sublethal effects of "Tree and Shrub"™ ("T+S"), a commercial insecticide containing the neonicotinoid imidacloprid as its active ingredient, on Caenorhabditis elegans. We discovered that "T+S" significantly stunted the overall growth in wildtype nematodes, an effect that was exacerbated by concurrent exposure to heat stress. "T+S" also negatively impacted fecundity as measured by increased germline apoptosis, a decrease in egg-laying, and fewer viable offspring. Lastly, exposure to "T+S" resulted in degenerative changes in nicotinic cholinergic neurons in wildtype nematodes. As a whole, these findings demonstrate widespread toxic effects of neonicotinoids to critical functions in nematodes.


Assuntos
Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/fisiologia , Inseticidas/toxicidade , Locomoção/efeitos dos fármacos , Neonicotinoides/toxicidade , Animais , Apoptose/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/metabolismo , Aberrações Cromossômicas , Fertilidade/efeitos dos fármacos , Células Germinativas/citologia , Células Germinativas/efeitos dos fármacos , Resposta ao Choque Térmico , Degeneração Neural/patologia , Oviposição/efeitos dos fármacos , Reprodução/efeitos dos fármacos
6.
Neurology ; 95(14): e1918-e1931, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32887784

RESUMO

OBJECTIVE: To characterize lesion evolution and neurodegeneration in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) using multimodal MRI. METHODS: We prospectively performed MRI and cognitive testing in RVCL-S and healthy control cohorts. Gray and white matter volume and disruption of white matter microstructure were quantified. Asymmetric spin echo acquisition permitted voxel-wise oxygen extraction fraction (OEF) calculation as an in vivo marker of microvascular ischemia. The RVCL-S cohort was included in a longitudinal analysis of lesion subtypes in which hyperintense lesions on fluid-attenuated inversion recovery (FLAIR), T1-postgadolinium, and diffusion-weighted imaging were delineated and quantified volumetrically. RESULTS: Twenty individuals with RVCL-S and 26 controls were enrolled. White matter volume and microstructure declined faster in those with RVCL-S compared to controls. White matter atrophy in RVCL-S was highly linear (ρ = -0.908, p < 0.0001). Normalized OEF was elevated in RVCL-S and increased with disease duration. Multiple cognitive domains, specifically those measuring working memory and processing speed, were impaired in RVCL-S. Lesion volumes, regardless of subtype, progressed/regressed with high variability as a function of age, while FLAIR lesion burden increased near time to death (p < 0.001). CONCLUSION: RVCL-S is a monogenic microvasculopathy affecting predominantly the white matter with regard to atrophy and cognitive impairment. White matter volumes in RVCL-S declined linearly, providing a potential metric against which to test the efficacy of future therapies. Progressive elevation of white matter OEF suggests that microvascular ischemia may underlie neurodegeneration in RVCL-S.


Assuntos
Disfunção Cognitiva/patologia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Degeneração Neural/patologia , Doenças Retinianas/patologia , Doenças Vasculares/patologia , Substância Branca/patologia , Adulto , Disfunção Cognitiva/diagnóstico por imagem , Feminino , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Degeneração Neural/diagnóstico por imagem , Neuroimagem/métodos , Doenças Retinianas/diagnóstico por imagem , Doenças Vasculares/diagnóstico por imagem , Substância Branca/diagnóstico por imagem
7.
Brain ; 143(7): 2295-2311, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32666090

RESUMO

Under the ATN framework, CSF analytes provide evidence of the presence or absence of Alzheimer's disease pathological hallmarks: amyloid plaques (A), phosphorylated tau (T), and accompanying neurodegeneration (N). Still, differences in CSF levels across amnestic and non-amnestic variants or due to co-occurring pathologies might lead to misdiagnoses. We assess the diagnostic accuracy of CSF markers for amyloid, tau, and neurodegeneration in an autopsy cohort of 118 Alzheimer's disease patients (98 amnestic; 20 non-amnestic) and 64 frontotemporal lobar degeneration patients (five amnestic; 59 non-amnestic). We calculated between-group differences in CSF concentrations of amyloid-ß1-42 peptide, tau protein phosphorylated at threonine 181, total tau, and the ratio of phosphorylated tau to amyloid-ß1-42. Results show that non-amnestic Alzheimer's disease patients were less likely to be correctly classified under the ATN framework using independent, published biomarker cut-offs for positivity. Amyloid-ß1-42 did not differ between amnestic and non-amnestic Alzheimer's disease, and receiver operating characteristic curve analyses indicated that amyloid-ß1-42 was equally effective in discriminating both groups from frontotemporal lobar degeneration. However, CSF concentrations of phosphorylated tau, total tau, and the ratio of phosphorylated tau to amyloid-ß1-42 were significantly lower in non-amnestic compared to amnestic Alzheimer's disease patients. Receiver operating characteristic curve analyses for these markers showed reduced area under the curve when discriminating non-amnestic Alzheimer's disease from frontotemporal lobar degeneration, compared to discrimination of amnestic Alzheimer's disease from frontotemporal lobar degeneration. In addition, the ATN framework was relatively insensitive to frontotemporal lobar degeneration, and these patients were likely to be classified as having normal biomarkers or biomarkers suggestive of primary Alzheimer's disease pathology. We conclude that amyloid-ß1-42 maintains high sensitivity to A status, although with lower specificity, and this single biomarker provides better sensitivity to non-amnestic Alzheimer's disease than either the ATN framework or the phosphorylated-tau/amyloid-ß1-42 ratio. In contrast, T and N status biomarkers differed between amnestic and non-amnestic Alzheimer's disease; standard cut-offs for phosphorylated tau and total tau may thus result in misclassifications for non-amnestic Alzheimer's disease patients. Consideration of clinical syndrome may help improve the accuracy of ATN designations for identifying true non-amnestic Alzheimer's disease.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Degeneração Lobar Frontotemporal/líquido cefalorraquidiano , Degeneração Lobar Frontotemporal/diagnóstico , Idoso , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Feminino , Degeneração Lobar Frontotemporal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Degeneração Neural/patologia , Sensibilidade e Especificidade , Proteínas tau/líquido cefalorraquidiano
8.
Sci Rep ; 10(1): 10802, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32612112

RESUMO

In vivo confocal microscopy (IVCM) imaging of the corneal subbasal nerve plexus (SBNP) is a clinical imaging modality gaining popularity for the diagnosis and follow-up of corneal neuropathy in various conditions such as diabetes mellitus. There remain, however, major limitations to the method, hindering its widespread clinical use. Finding the same exact area of the central cornea to standardize image acquisition is difficult without a reference point. Alternatively, creating wide-area mosaics of the SBNP is resource-intensive and has not yet been developed for routine clinical use. Here, we investigated whether IVCM analysis of the corneal SBNP in a predetermined, anatomically standardized region of interest (ROI) could be applied as an equivalent substitution for wide-area SBNP mosaic generation and analysis. Furthermore, we investigated nerve patterns outside the central corneal region for a possible relationship to type 2 diabetes mellitus status using a publicly available dataset. We found that corneal nerve fibre length density (CNFL) based on the ROI underestimated the mosaic-based CNFL by an average of 34% in 90% of cases (150 eyes), and did not exhibit a significant reduction with diabetes, as seen in the full SBNP. Outside the central cornea, nerve orientation differed depending on the anatomic region (left, central or right superior plexus, P < 0.001). Moreover, in long-term type 2 diabetes mellitus (≥ 10 years, 28 subjects), nerve density in the left superior sector of the SBNP was decreased (P < 0.001) while that in the central superior SBNP increased (P = 0.01) relative to 35 age-matched healthy subjects with normal glucose tolerance. These results indicate that subbasal nerve degeneration in type 2 diabetes mellitus can vary according to anatomic location, and regions with potential diagnostic value outside the central SBNP may warrant further investigation.


Assuntos
Córnea , Complicações do Diabetes/patologia , Diabetes Mellitus Tipo 2 , Degeneração Neural/patologia , Fibras Nervosas/patologia , Adulto , Córnea/inervação , Córnea/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Microscopia Intravital , Masculino , Microscopia Confocal , Pessoa de Meia-Idade
9.
Neurology ; 95(8): e943-e952, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32646955

RESUMO

OBJECTIVE: To evaluate progressive white matter (WM) degeneration in amyotrophic lateral sclerosis (ALS). METHODS: Sixty-six patients with ALS and 43 healthy controls were enrolled in a prospective, longitudinal, multicenter study in the Canadian ALS Neuroimaging Consortium (CALSNIC). Participants underwent a harmonized neuroimaging protocol across 4 centers that included diffusion tensor imaging (DTI) for assessment of WM integrity. Three visits were accompanied by clinical assessments of disability (ALS Functional Rating Scale-Revised [ALSFRS-R]) and upper motor neuron (UMN) function. Voxel-wise whole-brain and quantitative tract-wise DTI assessments were done at baseline and longitudinally. Correction for site variance incorporated data from healthy controls and from healthy volunteers who underwent the DTI protocol at each center. RESULTS: Patients with ALS had a mean progressive decline in fractional anisotropy (FA) of the corticospinal tract (CST) and frontal lobes. Tract-wise analysis revealed reduced FA in the CST, corticopontine/corticorubral tract, and corticostriatal tract. CST FA correlated with UMN function, and frontal lobe FA correlated with the ALSFRS-R score. A progressive decline in CST FA correlated with a decline in the ALSFRS-R score and worsening UMN signs. Patients with fast vs slow progression had a greater reduction in FA of the CST and upper frontal lobe. CONCLUSIONS: Progressive WM degeneration in ALS is most prominent in the CST and frontal lobes and, to a lesser degree, in the corticopontine/corticorubral tracts and corticostriatal pathways. With the use of a harmonized imaging protocol and incorporation of analytic methods to address site-related variances, this study is an important milestone toward developing DTI biomarkers for cerebral degeneration in ALS. CLINICALTRIALSGOV IDENTIFIER: NCT02405182.


Assuntos
Esclerose Amiotrófica Lateral/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Tratos Piramidais/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Adulto , Idoso , Esclerose Amiotrófica Lateral/patologia , Córtex Cerebral/patologia , Imagem de Tensor de Difusão , Progressão da Doença , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Degeneração Neural/diagnóstico por imagem , Degeneração Neural/patologia , Neuroimagem/métodos , Estudos Prospectivos , Tratos Piramidais/patologia , Substância Branca/patologia
10.
Cell Mol Life Sci ; 77(24): 5171-5188, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32617639

RESUMO

Glial cells have been identified more than 100 years ago, and are known to play a key role in the central nervous system (CNS) function. A recent piece of evidence is emerging showing that in addition to the capacity of CNS modulation and homeostasis, glial cells are also being looked like as a promising cell source not only to study CNS pathologies initiation and progression but also to the establishment and development of new therapeutic strategies. Thus, in the present review, we will discuss the current evidence regarding glial cells' contribution to neurodegenerative diseases as Parkinson's disease, providing cellular, molecular, functional, and behavioral data supporting its active role in disease initiation, progression, and treatment. As so, considering their functional relevance, glial cells may be important to the understanding of the underlying mechanisms regarding neuronal-glial networks in neurodegeneration/regeneration processes, which may open new research opportunities for their future use as a target or treatment in human clinical trials.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Neuroglia/transplante , Neurônios/transplante , Doença de Parkinson/terapia , Sistema Nervoso Central/patologia , Humanos , Degeneração Neural/patologia , Degeneração Neural/terapia , Neurônios/patologia , Doença de Parkinson/patologia
11.
J Vis Exp ; (159)2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32478750

RESUMO

Drosophila serves as a useful model for assessing synaptic structure and function associated with neurodegenerative diseases. While much work has focused on neuromuscular junctions (NMJs) in Drosophila larvae, assessing synaptic integrity in adult Drosophila has received much less attention. Here we provide a straightforward method for dissection of the dorsal longitudinal muscles (DLMs), which are required for flight ability. In addition to flight as a behavioral readout, this dissection allows for the both DLM synapses and muscle tissue to be amenable to structural analysis using fluorescently labeled antibodies for synaptic markers or proteins of interest. This protocol allows for the evaluation of the structural integrity of synapses in adult Drosophila during aging to model the progressive, age-dependent nature of most neurodegenerative diseases.


Assuntos
Envelhecimento/patologia , Drosophila melanogaster/fisiologia , Degeneração Neural/patologia , Sinapses/metabolismo , Esclerose Amiotrófica Lateral/patologia , Animais , Animais Geneticamente Modificados , Denervação , Dissecação , Congelamento , Humanos , Larva/metabolismo , Junção Neuromuscular/fisiologia , Coloração e Rotulagem , Tórax
12.
Cell Mol Life Sci ; 77(23): 4827-4845, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32500266

RESUMO

Stress Granules (SGs) are membraneless cytoplasmic RNA granules, which contain translationally stalled mRNAs, associated translation initiation factors and multiple RNA-binding proteins (RBPs). They are formed in response to various stresses and contribute to reprogramming of cellular metabolism to aid cell survival. Because of their cytoprotective nature, association with translation regulation and cell signaling, SGs are an essential component of the integrated stress response pathway, a complex adaptive program central to stress management. Recent advances in SG biology unambiguously demonstrate that SGs are heterogeneous in their RNA and protein content leading to the idea that various SG subtypes exist. These SG variants are formed in cell type- and stress-specific manners and differ in their composition, dynamics of assembly and disassembly, and contribution to cell viability. As aberrant SG dynamics contribute to the formation of pathological persistent SGs that are implicated in neurodegenerative diseases, the biology of different SG subtypes may be directly implicated in neurodegeneration. Here, we will discuss mechanisms of SG formation, their subtypes, and potential contribution to health and disease.


Assuntos
Grânulos Citoplasmáticos/metabolismo , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Animais , Compartimento Celular , Humanos , RNA/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transcriptoma/genética
13.
Neurology ; 95(1): e46-e58, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32522798

RESUMO

OBJECTIVE: To investigate the relationship between the ATN classification system (amyloid, tau, neurodegeneration) and risk of dementia and cognitive decline in individuals with subjective cognitive decline (SCD). METHODS: We classified 693 participants with SCD (60 ± 9 years, 41% women, Mini-Mental State Examination score 28 ± 2) from the Amsterdam Dementia Cohort and Subjective Cognitive Impairment Cohort (SCIENCe) project according to the ATN model, as determined by amyloid PET or CSF ß-amyloid (A), CSF p-tau (T), and MRI-based medial temporal lobe atrophy (N). All underwent extensive neuropsychological assessment. For 342 participants, follow-up was available (3 ± 2 years). As a control population, we included 124 participants without SCD. RESULTS: Fifty-six (n = 385) participants had normal Alzheimer disease (AD) biomarkers (A-T-N-), 27% (n = 186) had non-AD pathologic change (A-T-N+, A-T+N-, A-T+N+), 18% (n = 122) fell within the Alzheimer continuum (A+T-N-, A+T-N+, A+T+N-, A+T+N+). ATN profiles were unevenly distributed, with A-T+N+, A+T-N+, and A+T+N+ containing very few participants. Cox regression showed that compared to A-T-N-, participants in A+ profiles had a higher risk of dementia with a dose-response pattern for number of biomarkers affected. Linear mixed models showed participants in A+ profiles showed a steeper decline on tests addressing memory, attention, language, and executive functions. In the control group, there was no association between ATN and cognition. CONCLUSIONS: Among individuals presenting with SCD at a memory clinic, those with a biomarker profile A-T+N+, A+T-N-, A+T+N-, and A+T+N+ were at increased risk of dementia, and showed steeper cognitive decline compared to A-T-N- individuals. These results suggest a future where biomarker results could be used for individualized risk profiling in cognitively normal individuals presenting at a memory clinic.


Assuntos
Doença de Alzheimer , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/classificação , Progressão da Doença , Idoso , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Degeneração Neural/patologia , Proteínas tau/líquido cefalorraquidiano
14.
Neurochirurgie ; 66(3): 155-161, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32387429

RESUMO

BACKGROUND: The neuropathological mechanism of heart rhythm disorders, following spinal cord pathologies, to our knowledge, has not yet been adequately investigated. In this study, the effect of the ischemic neurodegeneration of the thoracic sympathetic nuclei (TSN) on the heart rate (HR) was examined following a spinal subarachnoid hemorrhage (SSAH). METHODS: This study was conducted on 22 rabbits. Five rabbits were used as a control group, five as SHAM, and twelve as a study group. The animals' HRs were recorded via monitoring devices on the first day, and those results were accepted as baseline values. The HRs were remeasured after injecting 0.5 cc of isotonic saline for SHAM and 0.5 cc of autolog arterial blood into the thoracic spinal subarachnoid space at T4-T5 for the study group. After a three-week follow-up with continuous monitoring of their HRs, the rabbit's thoracic spinal cords and stellate ganglia were extracted. The specimens were evaluated by histopathological methods. The densities of degenerated neurons in the TSN and stellate ganglia were compared with the HRs. RESULTS: The mean HRs and mean degenerated neuron density of the TSN and stellate ganglia in control group were 251±18/min, 5±2/mm3, and 3±1/mm3, respectively. The mean HRs and the mean degenerated neuron density of the TSN and stellate ganglia were detected as 242±13/min, 6±2/mm3, and 4±2/mm3 in SHAM (P>0.05 vs. control); 176±19/min, 94±12/mm3, and 28±6/mm3 in the study group (P<0.0001 vs. control and P<0.005 vs. SHAM), respectively. CONCLUSIONS: SAH induced TSN neurodegeneration may have been responsible for low HRs following SSAH. To date this has not been mentioned in the literature.


Assuntos
Gânglios Simpáticos/irrigação sanguínea , Gânglios Simpáticos/fisiopatologia , Frequência Cardíaca , Hemorragia Subaracnóidea/fisiopatologia , Animais , Apoptose , Isquemia , Masculino , Degeneração Neural/patologia , Neurônios/patologia , Coelhos , Medula Espinal/patologia , Gânglio Estrelado/patologia , Hemorragia Subaracnóidea/patologia
15.
Am J Pathol ; 190(8): 1713-1722, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32371051

RESUMO

Amyotrophic lateral sclerosis is a rapidly progressing and fatal disease characterized by muscular atrophy due to loss of upper and lower motor neurons. Pathogenic mutations in the TARDBP gene encoding TAR DNA binding protein-43 (TDP-43) have been identified in familial amyotrophic lateral sclerosis. We have previously reported transgenic mice with neuronal expression of human TDP-43 carrying the pathogenic A315T mutation (iTDP-43A315T mice) using a tetracycline-controlled inducible promotor system. Constitutive expression of transgenic TDP-43A315T in the absence of doxycycline resulted in pronounced early-onset and progressive neurodegeneration, and motor and memory deficits. Here, delayed transgene expression of TDP-43A315T by oral doxycycline treatment of iTDP-43A315T mice from birth till weaning was analyzed. After doxycycline withdrawal, transgenic TDP-43A315T expression gradually increased and resulted in cytoplasmic TDP-43, widespread ubiquitination, and cortical and hippocampal atrophy. In addition, these mice developed motor and gait deficits with underlying muscle atrophy, similar to that observed in the constitutive iTDP-43A315T mice. Surprisingly, in contrast to the constitutive iTDP-43A315T mice, these mice did not develop astrogliosis. In summary, delayed activation coupled with gradual increase in TDP-43A315T expression in the central nervous system of mature mice resulted in progressive functional deficits with neuron and muscle loss, but in the absence of a glial response. This suggests that astrocytosis does not contribute to functional deficits and neuronal loss upon TDP-43A315T expression in mature mice.


Assuntos
Encéfalo/metabolismo , Proteínas de Ligação a DNA/genética , Gliose/patologia , Transtornos Motores/genética , Atrofia Muscular/genética , Degeneração Neural/genética , Animais , Encéfalo/patologia , Proteínas de Ligação a DNA/metabolismo , Camundongos , Camundongos Transgênicos , Transtornos Motores/metabolismo , Transtornos Motores/patologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Degeneração Neural/metabolismo , Degeneração Neural/patologia
16.
Neuron ; 107(1): 65-81.e9, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32375064

RESUMO

Many therapies for lysosomal storage disorders rely on cross-correction of lysosomal enzymes. In globoid cell leukodystrophy (GLD), mutations in GALC cause psychosine accumulation, inducing demyelination, a neuroinflammatory "globoid" reaction and neurodegeneration. The efficiency of GALC cross-correction in vivo, the role of the GALC substrate galactosylceramide, and the origin of psychosine are poorly understood. Using a novel GLD model, we show that cross-correction does not occur efficiently in vivo and that Galc-deficient Schwann cells autonomously produce psychosine. Furthermore, macrophages require GALC to degrade myelin, as Galc-deficient macrophages are transformed into globoid cells by exposure to galactosylceramide and produce a more severe GLD phenotype. Finally, hematopoietic stem cell transplantation in patients reduces globoid cells in nerves, suggesting that the phagocytic response of healthy macrophages, rather than cross-correction, contributes to the therapeutic effect. Thus, GLD may be caused by at least two mechanisms: psychosine-induced demyelination and secondary neuroinflammation from galactosylceramide storage in macrophages.


Assuntos
Galactosilceramidase/metabolismo , Leucodistrofia de Células Globoides/enzimologia , Macrófagos/enzimologia , Células de Schwann/enzimologia , Animais , Doenças Desmielinizantes/enzimologia , Doenças Desmielinizantes/patologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucodistrofia de Células Globoides/patologia , Leucodistrofia de Células Globoides/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Degeneração Neural/enzimologia , Degeneração Neural/patologia
17.
Brain ; 143(8): 2369-2379, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32355960

RESUMO

Hereditary spastic paraplegia (HSP) is a heterogeneous group of rare motor neuron disorders characterized by progressive weakness and spasticity of the lower limbs. HSP type 11 (SPG11-HSP) is linked to pathogenic variants in the SPG11 gene and it represents the most frequent form of complex autosomal recessive HSP. The majority of SPG11-HSP patients exhibit additional neurological symptoms such as cognitive decline, thin corpus callosum, and peripheral neuropathy. Yet, the mechanisms of SPG11-linked spectrum diseases are largely unknown. Recent findings indicate that spatacsin, the 280 kDa protein encoded by SPG11, may impact the autophagy-lysosomal machinery. In this update, we summarize the current knowledge of SPG11-HSP. In addition to clinical symptoms and differential diagnosis, our work aims to link the different clinical manifestations with the respective structural abnormalities and cellular in vitro phenotypes. Moreover, we describe the impact of localization and function of spatacsin in different neuronal systems. Ultimately, we propose a model in which spatacsin bridges between neurodevelopmental and neurodegenerative phenotypes of SPG11-linked disorders.


Assuntos
Degeneração Neural/genética , Transtornos do Neurodesenvolvimento/genética , Proteínas/genética , Paraplegia Espástica Hereditária/genética , Animais , Humanos , Mutação , Degeneração Neural/patologia , Fenótipo , Paraplegia Espástica Hereditária/patologia
18.
Brain ; 143(5): 1350-1367, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358598

RESUMO

Many RNA-binding proteins, including TDP-43, FUS, and TIA1, are stress granule components, dysfunction of which causes amyotrophic lateral sclerosis (ALS). However, whether a mutant RNA-binding protein disrupts stress granule processing in vivo in pathogenesis is unknown. Here we establish a FUS ALS mutation, p.R521C, knock-in mouse model that carries impaired motor ability and late-onset motor neuron loss. In disease-susceptible neurons, stress induces mislocalization of mutant FUS into stress granules and upregulation of ubiquitin, two hallmarks of disease pathology. Additionally, stress aggravates motor performance decline in the mutant mouse. By using two-photon imaging in TIA1-EGFP transduced animals, we document more intensely TIA1-EGFP-positive granules formed hours but cleared weeks after stress challenge in neurons in the mutant cortex. Moreover, neurons with severe granule misprocessing die days after stress challenge. Therefore, we argue that stress granule misprocessing is pathogenic in ALS, and the model we provide here is sound for further disease mechanistic study.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Encéfalo/metabolismo , Grânulos Citoplasmáticos/metabolismo , Neurônios Motores/metabolismo , Proteína FUS de Ligação a RNA/genética , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Animais , Encéfalo/patologia , Grânulos Citoplasmáticos/patologia , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Camundongos , Neurônios Motores/patologia , Mutação , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Estresse Fisiológico/fisiologia
19.
Biochem Biophys Res Commun ; 526(4): 1013-1020, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32321640

RESUMO

Parkinson's disease (PD) is neurodegenerative disease, featured by a loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), characteristic motor symptoms and cognitive impairment. Development of effective therapeutic drugs for PD is necessary. In this study, we investigated the potential of Bruceine D (BD) during PD progression. After establishment of PD mouse models, we found that BD markedly improved the motor function of mice and alleviated chemically induced dopaminergic neuron loss of tyrosine hydroxylase (TH) in the SNpc area. BD treatments markedly repressed the neuroinflammation in SNpc by restricting nuclear factor κB (NF-κB) activation, accompanied with the reduced activity of astrocytes and microglial. BD also improved the antioxidant system in MPTP-challenged mice, as proved by the up-regulated superoxide dismutase (SOD) and glutathione (GSH), and down-regulated malondialdehyde (MDA) in SNpc and striatum (STR). The anti-oxidant effects of BD were regulated by the activation of nuclear factor E2-related factor 2 (Nrf2) signaling, contributing to the expression of Nrf2 down-streaming signals such as heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase 1 (NQO1) and glutathione cysteine ligase modulatory subunit (GCLM). In MPP+-challenged mouse neurons, BD exhibited cytoprotective effects by improving the Nrf2-meditated antioxidant system and abolished the MPP+-triggered inflammatory response through hindering the activation of the NF-κB signal. The pharmacokinetic parameters and organ distribution findings demonstrated that BD showed a brain tissue targeting function. Moreover, both in vivo and in vitro analysis indicated that BD had few side effects. Collectively, results here demonstrated that BD was effective for the inhibition of dopaminergic neuronal loss and PD progression by activating Nrf2 without toxicity.


Assuntos
Inflamação/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Quassinas/farmacologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/patologia , Masculino , Camundongos Endogâmicos C57BL , Degeneração Neural/patologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Quassinas/química , Transdução de Sinais/efeitos dos fármacos
20.
Neuron ; 107(1): 82-94.e6, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32330411

RESUMO

Patients lacking PYCR2, a mitochondrial enzyme that synthesizes proline, display postnatal degenerative microcephaly with hypomyelination. Here we report the crystal structure of the PYCR2 apo-enzyme and show that a novel germline p.Gly249Val mutation lies at the dimer interface and lowers its enzymatic activity. We find that knocking out Pycr2 in mice phenocopies the human disorder and depletes PYCR1 levels in neural lineages. In situ quantification of neurotransmitters in the brains of PYCR2 mutant mice and patients revealed a signature of encephalopathy driven by excessive cerebral glycine. Mechanistically, we demonstrate that loss of PYCR2 upregulates SHMT2, which is responsible for glycine synthesis. This hyperglycemia could be partially reversed by SHMT2 knockdown, which rescued the axonal beading and neurite lengths of cultured Pycr2 knockout neurons. Our findings identify the glycine metabolic pathway as a possible intervention point to alleviate the neurological symptoms of PYCR2-mutant patients.


Assuntos
Córtex Cerebral/metabolismo , Glicina Hidroximetiltransferase/metabolismo , Glicina/metabolismo , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Pirrolina Carboxilato Redutases/genética , Adolescente , Animais , Córtex Cerebral/patologia , Pré-Escolar , Feminino , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/metabolismo , Humanos , Lactente , Masculino , Camundongos , Camundongos Knockout , Degeneração Neural/genética , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Linhagem , Pirrolina Carboxilato Redutases/deficiência
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