Cytokine dysregulation is believed to play a key role in the remodeling of the immune system at older age, with evidence pointing to an inability to fine-control systemic inflammation, which seems to ...be a marker of unsuccessful aging. This reshaping of cytokine expression pattern, with a progressive tendency toward a pro-inflammatory phenotype has been called "inflamm-aging." Despite research there is no clear understanding about the causes of "inflamm-aging" that underpin most major age-related diseases, including atherosclerosis, diabetes, Alzheimer's disease, rheumatoid arthritis, cancer, and aging itself. While inflammation is part of the normal repair response for healing, and essential in keeping us safe from bacterial and viral infections and noxious environmental agents, not all inflammation is good. When inflammation becomes prolonged and persists, it can become damaging and destructive. Several common molecular pathways have been identified that are associated with both aging and low-grade inflammation. The age-related change in redox balance, the increase in age-related senescent cells, the senescence-associated secretory phenotype (SASP) and the decline in effective autophagy that can trigger the inflammasome, suggest that it may be possible to delay age-related diseases and aging itself by suppressing pro-inflammatory molecular mechanisms or improving the timely resolution of inflammation. Conversely there may be learning from molecular or genetic pathways from long-lived cohorts who exemplify good quality aging. Here, we will discuss some of the current ideas and highlight molecular pathways that appear to contribute to the immune imbalance and the cytokine dysregulation, which is associated with "inflammageing" or parainflammation. Evidence of these findings will be drawn from research in cardiovascular disease, cancer, neurological inflammation and rheumatoid arthritis.
Synucleinopathies are clinically and pathologically heterogeneous disorders characterized by pathologic aggregates of α-synuclein in neurons and glia, in the form of Lewy bodies, Lewy neurites, ...neuronal cytoplasmic inclusions, and glial cytoplasmic inclusions. Synucleinopathies can be divided into two major disease entities: Lewy body disease and multiple system atrophy (MSA). Common clinical presentations of Lewy body disease are Parkinson's disease (PD), PD with dementia, and dementia with Lewy bodies (DLB), while MSA has two major clinical subtypes, MSA with predominant cerebellar ataxia and MSA with predominant parkinsonism. There are currently no disease-modifying therapies for the synucleinopathies, but information obtained from molecular genetics and models that explore mechanisms of α-synuclein conversion to pathologic oligomers and insoluble fibrils offer hope for eventual therapies. It remains unclear how α-synuclein can be associated with distinct cellular pathologies (e.g., Lewy bodies and glial cytoplasmic inclusions) and what factors determine neuroanatomical and cell type vulnerability. Accumulating evidence from in vitro and in vivo experiments suggests that α-synuclein species derived from Lewy body disease and MSA are distinct "strains" having different seeding properties. Recent advancements in in vitro seeding assays, such as real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), not only demonstrate distinct seeding activity in the synucleinopathies, but also offer exciting opportunities for molecular diagnosis using readily accessible peripheral tissue samples. Cryogenic electron microscopy (cryo-EM) structural studies of α-synuclein derived from recombinant or brain-derived filaments provide new insight into mechanisms of seeding in synucleinopathies. In this review, we describe clinical, genetic and neuropathologic features of synucleinopathies, including a discussion of the evolution of classification and staging of Lewy body disease. We also provide a brief discussion on proposed mechanisms of Lewy body formation, as well as evidence supporting the existence of distinct α-synuclein strains in Lewy body disease and MSA.
Summary Background Neurofibrillary pathology has a stereotypical progression in Alzheimer's disease (AD) that is encapsulated in the Braak staging scheme; however, some AD cases are atypical and do ...not fit into this scheme. We aimed to compare clinical and neuropathological features between typical and atypical AD cases. Methods AD cases with a Braak neurofibrillary tangle stage of more than IV were identified from a brain bank database. By use of thioflavin-S fluorescence microscopy, we assessed the density and the distribution of neurofibrillary tangles in three cortical regions and two hippocampal sectors. These data were used to construct an algorithm to classify AD cases into typical, hippocampal sparing, or limbic predominant. Classified cases were then compared for clinical, demographic, pathological, and genetic characteristics. An independent cohort of AD cases was assessed to validate findings from the initial cohort. Findings 889 cases of AD, 398 men and 491 women with age at death of 37–103 years, were classified with the algorithm as hippocampal sparing (97 cases 11%), typical (665 75%), or limbic predominant (127 14%). By comparison with typical AD, neurofibrillary tangle counts per 0.125 mm2 in hippocampal sparing cases were higher in cortical areas (median 13, IQR 11–16) and lower in the hippocampus (7.5, 5.2–9.5), whereas counts in limbic-predominant cases were lower in cortical areas (4.3, 3.0–5.7) and higher in the hippocampus (27, 22–35). Hippocampal sparing cases had less hippocampal atrophy than did typical and limbic-predominant cases. Patients with hippocampal sparing AD were younger at death (mean 72 years SD 10) and a higher proportion of them were men (61 63%), whereas those with limbic-predominant AD were older (mean 86 years SD 6) and a higher proportion of them were women (87 69%). Microtubule-associated protein tau ( MAPT ) H1H1 genotype was more common in limbic-predominant AD (54 70%) than in hippocampal sparing AD (24 46%; p=0.011), but did not differ significantly between limbic-predominant and typical AD (204 59%; p=0.11). Apolipoprotein E ( APOE ) ε4 allele status differed between AD subtypes only when data were stratified by age at onset. Clinical presentation, age at onset, disease duration, and rate of cognitive decline differed between the AD subtypes. These findings were confirmed in a validation cohort of 113 patients with AD. Interpretation These data support the hypothesis that AD has distinct clinicopathological subtypes. Hippocampal sparing and limbic-predominant AD subtypes might account for about 25% of cases, and hence should be considered when designing clinical, genetic, biomarker, and treatment studies in patients with AD. Funding US National Institutes of Health via Mayo Alzheimer's Disease Research Center, Mayo Clinic Study on Aging, Florida Alzheimer's Disease Research Center, and Einstein Aging Study; and State of Florida Alzheimer's Disease Initiative.
Abstract The discovery in 1997 that mutations in the SNCA gene cause Parkinson's disease (PD) greatly advanced our understanding of this illness. There are pathogenic missense mutations and ...multiplication mutations in SNCA . Thus, not only a mutant protein, but also an increased dose of wild-type protein can produce autosomal dominant parkinsonism. We review the literature on SNCA duplications and focus on pathologically-confirmed cases. We also report a newly-identified American family with SNCA duplication whose proband was autopsied. We found that over half of the reported cases with SNCA duplication had early-onset parkinsonism and non-motor features, such as dysautonomia, rapid eye movement sleep behavior disorder (RBD), hallucinations (usually visual) and cognitive deficits leading to dementia. Only a few cases have presented with typical features of PD. Our case presented with depression and RBD that preceded parkinsonism, and dysautonomia that led to an initial diagnosis of multiple system atrophy. Dementia and visual hallucinations followed. Our patient and the other reported cases with SNCA duplications had widespread cortical Lewy pathology. Neuronal loss in the hippocampal cornu ammonis 2/3 regions were seen in about half of the autopsied SNCA duplication cases. Similar pathology was also observed in SNCA missense mutation and triplication carriers.
Epigenetic regulation in Parkinson’s disease Labbé, Catherine; Lorenzo-Betancor, Oswaldo; Ross, Owen A.
Acta Neuropathologica,
10/2016, Letnik:
132, Številka:
4
Journal Article, Book Review
Recenzirano
Odprti dostop
Recent efforts have shed new light on the epigenetic mechanisms driving gene expression alterations associated with Parkinson’s disease (PD) pathogenesis. Changes in gene expression are a ...well-established cause of PD, and epigenetic mechanisms likely play a pivotal role in regulation. Studies in families with PD harboring duplications and triplications of the
SNCA
gene have demonstrated that gene dosage is associated with increased expression of both
SNCA
mRNA and protein, and correlates with a fulminant disease course. Furthermore, it is postulated that even subtle changes in
SNCA
expression caused by common variation is associated with disease risk. Of note, genome-wide association studies have identified over 30 loci associated with PD with most signals located in non-coding regions of the genome, thus likely influencing transcript expression levels. In health, epigenetic mechanisms tightly regulate gene expression, turning genes on and off to balance homeostasis and this, in part, explains why two cells with the same DNA sequence will have different RNA expression profiles. Understanding this phenomenon will be crucial to our interpretation of the selective vulnerability observed in neurodegeneration and specifically dopaminergic neurons in the PD brain. In this review, we discuss epigenetic mechanisms, such as DNA methylation and histone modifications, involved in regulating the expression of genes relevant to PD, RNA-based mechanisms, as well as the effect of toxins and potential epigenetic-based treatments for PD.
Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder linked to repetitive traumatic brain injury (TBI) and characterized by deposition of hyperphosphorylated tau at the ...depths of sulci. We sought to determine the presence of CTE pathology in a brain bank for neurodegenerative disorders for individuals with and without a history of contact sports participation. Available medical records of 1721 men were reviewed for evidence of past history of injury or participation in contact sports. Subsequently, cerebral cortical samples were processed for tau immunohistochemistry in cases with a documented history of sports exposure as well as age- and disease-matched men and women without such exposure. For cases with available frozen tissue, genetic analysis was performed for variants in
APOE
,
MAPT
, and
TMEM106B
. Immunohistochemistry revealed 21 of 66 former athletes had cortical tau pathology consistent with CTE. CTE pathology was not detected in 198 individuals without exposure to contact sports, including 33 individuals with documented single-incident TBI sustained from falls, motor vehicle accidents, domestic violence, or assaults. Among those exposed to contact sports, those with CTE pathology did not differ from those without CTE pathology with respect to noted clinicopathologic features. There were no significant differences in genetic variants for those with CTE pathology, but we observed a slight increase in
MAPT
H1 haplotype, and there tended to be fewer homozygous carriers of the protective
TMEM106B
rs3173615 minor allele in those with sports exposure and CTE pathology compared to those without CTE pathology. In conclusion, this study has identified a small, yet significant, subset of individuals with neurodegenerative disorders and concomitant CTE pathology. CTE pathology was only detected in individuals with documented participation in contact sports. Exposure to contact sports was the greatest risk factor for CTE pathology. Future studies addressing clinical correlates of CTE pathology are needed.
The human genome contains "dark" gene regions that cannot be adequately assembled or aligned using standard short-read sequencing technologies, preventing researchers from identifying mutations ...within these gene regions that may be relevant to human disease. Here, we identify regions with few mappable reads that we call dark by depth, and others that have ambiguous alignment, called camouflaged. We assess how well long-read or linked-read technologies resolve these regions.
Based on standard whole-genome Illumina sequencing data, we identify 36,794 dark regions in 6054 gene bodies from pathways important to human health, development, and reproduction. Of these gene bodies, 8.7% are completely dark and 35.2% are ≥ 5% dark. We identify dark regions that are present in protein-coding exons across 748 genes. Linked-read or long-read sequencing technologies from 10x Genomics, PacBio, and Oxford Nanopore Technologies reduce dark protein-coding regions to approximately 50.5%, 35.6%, and 9.6%, respectively. We present an algorithm to resolve most camouflaged regions and apply it to the Alzheimer's Disease Sequencing Project. We rescue a rare ten-nucleotide frameshift deletion in CR1, a top Alzheimer's disease gene, found in disease cases but not in controls.
While we could not formally assess the association of the CR1 frameshift mutation with Alzheimer's disease due to insufficient sample-size, we believe it merits investigating in a larger cohort. There remain thousands of potentially important genomic regions overlooked by short-read sequencing that are largely resolved by long-read technologies.
MAPT encodes the microtubule-associated protein tau, which is the main component of neurofibrillary tangles (NFTs) and found in other protein aggregates. These aggregates are among the pathological ...hallmarks of primary tauopathies such as frontotemporal dementia (FTD). Abnormal tau can also be observed in secondary tauopathies such as Alzheimer's disease (AD) and synucleinopathies such as Parkinson's disease (PD). On top of pathological findings, genetic data also links MAPT to these disorders. MAPT variations are a cause or risk factors for many tauopathies and synucleinopathies and are associated with certain clinical and pathological features in affected individuals. In addition to clinical, pathological, and genetic overlap, evidence also suggests that tau and alpha-synuclein may interact on the molecular level, and thus might collaborate in the neurodegenerative process. Understanding the role of MAPT variations in tauopathies and synucleinopathies is therefore essential to elucidate the role of tau in the pathogenesis and phenotype of those disorders, and ultimately to develop targeted therapies. In this review, we describe the role of MAPT genetic variations in tauopathies and synucleinopathies, several genotype-phenotype and pathological features, and discuss their implications for the classification and treatment of those disorders.
•MAPT encodes the microtubule associated protein tau.•Tau accumulates in disorders known as tauopathies, but also in other neurological diseases.•Rare and common genetic variants in MAPT may have different roles in these disorders.
VPS35 Mutations in Parkinson Disease Vilariño-Güell, Carles; Wider, Christian; Ross, Owen A. ...
American journal of human genetics,
07/2011, Letnik:
89, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The identification of genetic causes for Mendelian disorders has been based on the collection of multi-incident families, linkage analysis, and sequencing of genes in candidate intervals. This study ...describes the application of next-generation sequencing technologies to a Swiss kindred presenting with autosomal-dominant, late-onset Parkinson disease (PD). The family has tremor-predominant dopa-responsive parkinsonism with a mean onset of 50.6 ± 7.3 years. Exome analysis suggests that an aspartic-acid-to-asparagine mutation within vacuolar protein sorting 35 (VPS35 c.1858G>A; p.Asp620Asn) is the genetic determinant of disease. VPS35 is a central component of the retromer cargo-recognition complex, is critical for endosome-trans-golgi trafficking and membrane-protein recycling, and is evolutionarily highly conserved. VPS35 c.1858G>A was found in all affected members of the Swiss kindred and in three more families and one patient with sporadic PD, but it was not observed in 3,309 controls. Further sequencing of familial affected probands revealed only one other missense variant, VPS35 c.946C>T; (p.Pro316Ser), in a pedigree with one unaffected and two affected carriers, and thus the pathogenicity of this mutation remains uncertain. Retromer-mediated sorting and transport is best characterized for acid hydrolase receptors. However, the complex has many types of cargo and is involved in a diverse array of biologic pathways from developmental Wnt signaling to lysosome biogenesis. Our study implicates disruption of VPS35 and retromer-mediated trans-membrane protein sorting, rescue, and recycling in the neurodegenerative process leading to PD.
Mitochondrial crista structure partitions vital cellular reactions and is precisely regulated by diverse cellular signals. Here, we show that, in Drosophila, mitochondrial cristae undergo dynamic ...remodeling among distinct subcellular regions and the Parkinson’s disease (PD)-linked Ser/Thr kinase PINK1 participates in their regulation. Mitochondria increase crista junctions and numbers in selective subcellular areas, and this remodeling requires PINK1 to phosphorylate the inner mitochondrial membrane protein MIC60/mitofilin, which stabilizes MIC60 oligomerization. Expression of MIC60 restores crista structure and ATP levels of PINK1-null flies and remarkably rescues their behavioral defects and dopaminergic neurodegeneration. In an extension to human relevance, we discover that the PINK1-MIC60 pathway is conserved in human neurons, and expression of several MIC60 coding variants in the mitochondrial targeting sequence found in PD patients in Drosophila impairs crista junction formation and causes locomotion deficits. These findings highlight the importance of maintenance and plasticity of crista junctions to cellular homeostasis in vivo.
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•Mitochondria remodel crista junctions in selective subcellular areas in Drosophila•This structural remodeling requires PINK1 to phosphorylate MIC60•PINK1-mediated phosphorylation of MIC60 stabilizes MIC60 oligomerization•Rare coding variants of MIC60 found in Parkinson’s patients are damaging in flies
Tsai et al. discover that mitochondria increase crista junctions and numbers in selective subcellular areas in Drosophila. This structural remodeling requires Parkinson’s-linked PINK1 to phosphorylate the inner mitochondrial membrane protein MIC60, which stabilizes MIC60 oligomerization. MIC60 functions downstream of PINK1 to maintain mitochondrial functions and cellular survival.
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