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Cerebellar Expression of the Neurotrophin Receptor p75 in Naked-Ataxia Mutant Mouse

by Maryam Rahimi Balaei, Xiaodan Jiao, Niloufar Ashtari, Pegah Afsharinezhad, Saeid Ghavami and Hassan Marzban

Int. J. Mol. Sci. 2016, 17(1), 115; https://doi.org/10.3390/ijms17010115 - 15 Jan 2016

Cited by 13 | Viewed by 6960

Abstract

Spontaneous mutation in the lysosomal acid phosphatase 2 (Acp2) mouse (nax—naked-ataxia mutant mouse) correlates with severe cerebellar defects including ataxia, reduced size and abnormal lobulation as well as Purkinje cell (Pc) degeneration. Loss of Pcs in the nax cerebellum is compartmentalized [...] Read more.

Spontaneous mutation in the lysosomal acid phosphatase 2 (Acp2) mouse (nax—naked-ataxia mutant mouse) correlates with severe cerebellar defects including ataxia, reduced size and abnormal lobulation as well as Purkinje cell (Pc) degeneration. Loss of Pcs in the nax cerebellum is compartmentalized and harmonized to the classic pattern of gene expression of the cerebellum in the wild type mouse. Usually, degeneration starts in the anterior and posterior zones and continues to the central and nodular zones of cerebellum. Studies have suggested that the p75 neurotrophin receptor (NTR) plays a role in Pc degeneration; thus, in this study, we investigated the p75NTR pattern and protein expression in the cerebellum of the nax mutant mouse. Despite massive Pc degeneration that was observed in the nax mouse cerebellum, p75NTR pattern expression was similar to the HSP25 pattern in nax mice and comparable with wild type sibling cerebellum. In addition, immunoblot analysis of p75NTR protein expression did not show any significant difference between nax and wild type sibling (p > 0.5). In comparison with wild type counterparts, p75NTR pattern expression is aligned with the fundamental cytoarchitecture organization of the cerebellum and is unchanged in the nax mouse cerebellum despite the severe neurodevelopmental disorder accompanied with Pc degeneration. Full article

(This article belongs to the Special Issue Mechanisms of Neurodegeneration)

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Effects of Ethanol on the Expression Level of Various BDNF mRNA Isoforms and Their Encoded Protein in the Hippocampus of Adult and Embryonic Rats

by Shahla Shojaei, Saeid Ghavami, Mohammad Reza Panjehshahin and Ali Akbar Owji

Int. J. Mol. Sci. 2015, 16(12), 30422-30437; https://doi.org/10.3390/ijms161226242 - 21 Dec 2015

Cited by 12 | Viewed by 5642

Abstract

We aimed to compare the effects of oral ethanol (Eth) alone or combined with the phytoestrogen resveratrol (Rsv) on the expression of various brain-derived neurotrophic factor (BDNF) transcripts and the encoded protein pro-BDNF in the hippocampus of pregnant and embryonic rats. A low [...] Read more.

We aimed to compare the effects of oral ethanol (Eth) alone or combined with the phytoestrogen resveratrol (Rsv) on the expression of various brain-derived neurotrophic factor (BDNF) transcripts and the encoded protein pro-BDNF in the hippocampus of pregnant and embryonic rats. A low (0.25 g/kg body weight (BW)/day) dose of Eth produced an increase in the expression of BDNF exons I, III and IV and a decrease in that of the exon IX in embryos, but failed to affect BDNF transcript and pro-BDNF protein expression in adults. However, co-administration of Eth 0.25 g/kg·BW/day and Rsv led to increased expression of BDNF exons I, III and IV and to a small but significant increase in the level of pro-BDNF protein in maternal rats. A high (2.5 g/kg·BW/day) dose of Eth increased the expression of BDNF exons III and IV in embryos, but it decreased the expression of exon IX containing BDNF mRNAs in the maternal rats. While the high dose of Eth alone reduced the level of pro-BDNF in adults, it failed to change the levels of pro-BDNF in embryos. Eth differentially affects the expression pattern of BDNF transcripts and levels of pro-BDNF in the hippocampus of both adult and embryonic rats. Full article

(This article belongs to the Special Issue Mechanisms of Neurodegeneration)

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Open AccessArticle

Abnormal Paraplegin Expression in Swollen Neurites, τ- and α-Synuclein Pathology in a Case of Hereditary Spastic Paraplegia SPG7 with an Ala510Val Mutation

by Dietmar R. Thal, Stephan Züchner, Stephan Gierer, Claudia Schulte, Ludger Schöls, Rebecca Schüle and Matthis Synofzik

Int. J. Mol. Sci. 2015, 16(10), 25050-25066; https://doi.org/10.3390/ijms161025050 - 21 Oct 2015

Cited by 18 | Viewed by 7601

Abstract

Mutations in the SPG7 gene are the most frequent cause of autosomal recessive hereditary spastic paraplegias and spastic ataxias. Ala510Val is the most common SPG7 mutation, with a frequency of up to 1% in the general population. Here we report the clinical, genetic, [...] Read more.

Mutations in the SPG7 gene are the most frequent cause of autosomal recessive hereditary spastic paraplegias and spastic ataxias. Ala510Val is the most common SPG7 mutation, with a frequency of up to 1% in the general population. Here we report the clinical, genetic, and neuropathological findings in a homozygous Ala510Val SPG7 case with spastic ataxia. Neuron loss with associated gliosis was found in the inferior olivary nucleus, the dentate nucleus of the cerebellum, the substantia nigra and the basal nucleus of Meynert. Neurofilament and/or paraplegin accumulation was observed in swollen neurites in the cerebellar and cerebral cortex. This case also showed subcortical τ-pathology in an unique distribution pattern largely restricted to the brainstem. α-synuclein containing Lewy bodies (LBs) were observed in the brainstem and the cortex, compatible with a limbic pattern of Braak LB-Disease stage 4. Taken together, this case shows that the spectrum of pathologies in SPG7 can include neuron loss of the dentate nucleus and the inferior olivary nucleus as well as neuritic pathology. The progressive supranuclear palsy-like brainstem predominant pattern of τ pathology and α-synuclein containing Lewy bodies in our SPG7 cases may be either coincidental or related to SPG7 in addition to neuron loss and neuritic pathology. Full article

(This article belongs to the Special Issue Mechanisms of Neurodegeneration)

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Open AccessArticle

Mutational Spectrum Analysis of Neurodegenerative Diseases and Its Pathogenic Implication

by Liang Shen and Hong-Fang Ji

Int. J. Mol. Sci. 2015, 16(10), 24295-24301; https://doi.org/10.3390/ijms161024295 - 14 Oct 2015

Cited by 3 | Viewed by 5093

Abstract

One of the most conspicuous features of neurodegenerative diseases (NDs) is the occurrence of dramatic conformation change of individual proteins. We performed a mutational spectrum analysis of disease-causing missense mutations in seven types of NDs at nucleotide and amino acid levels, and compared [...] Read more.

One of the most conspicuous features of neurodegenerative diseases (NDs) is the occurrence of dramatic conformation change of individual proteins. We performed a mutational spectrum analysis of disease-causing missense mutations in seven types of NDs at nucleotide and amino acid levels, and compared the results with those of non-NDs. The main findings included: (i) The higher mutation ratio of G:C→T:A transversion to G:C→A:T transition was observed in NDs than in non-NDs, interpreting the excessive guanine-specific oxidative DNA damage in NDs; (ii) glycine and proline had highest mutability in NDs than in non-NDs, which favor the protein conformation change in NDs; (iii) surprisingly low mutation frequency of arginine was observed in NDs. These findings help to understand how mutations may cause NDs. Full article

(This article belongs to the Special Issue Mechanisms of Neurodegeneration)

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Open AccessArticle

ALS-Linked P56S-VAPB Mutation Impairs the Formation of Multinuclear Myotube in C2C12 Cells

by Yukako Tokutake, Keita Yamada, Masaki Ohata, Yoshihito Obayashi, Megumi Tsuchiya and Shinichi Yonekura

Int. J. Mol. Sci. 2015, 16(8), 18628-18641; https://doi.org/10.3390/ijms160818628 - 10 Aug 2015

Cited by 17 | Viewed by 7457

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder that affects upper and lower motor neurons. Since motor neurons target skeletal muscles, the maintenance system of muscles is disturbed in ALS; however, the mechanism by which this occurs is unknown. In the [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder that affects upper and lower motor neurons. Since motor neurons target skeletal muscles, the maintenance system of muscles is disturbed in ALS; however, the mechanism by which this occurs is unknown. In the present study, we investigated the effects of ALS-associated P56S-vesicle-associated membrane protein-associated protein B (VAPB) (P56S-VAPB) on the IRE1-XBP1 pathway, which is involved in the unfolded protein response (UPR) of the mouse myoblast cell line (C2C12 cells). Experiments with C2C12 cells transfected with wild-type wt-VAPB and P56S-VAPB expression vectors showed reduced myotube formation and aberrant myonuclear position in cells expressing P56S-VAPB. Activity of the IRE1-XBP1 pathway in the cells visualized with the ERAI system revealed that the pathway was disrupted in cells expressing P56S-VAPB, whereas the IRE1-XBP1 pathway activity was enhanced in the differentiation process of normal C2C12 cells. These results suggest that disruption of the IRE1-XBP1 pathway is a cause for the reduced myotube formation in P56S-VAPB-expressing cells. The expression level of the VAPB protein has been reported to be reduced in the neurons of patients with ALS. Therefore, it is expected that the IRE1-XBP1 pathway is also impaired in muscle tissues of patients with ALS, which causes a disturbance in the muscle maintenance system. Full article

(This article belongs to the Special Issue Mechanisms of Neurodegeneration)

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Impaired Focal Adhesion Kinase-Grb2 Interaction during Elevated Activity in Hippocampal Neurons

by Sachiko Murase

Int. J. Mol. Sci. 2015, 16(7), 15659-15669; https://doi.org/10.3390/ijms160715659 - 10 Jul 2015

Cited by 6 | Viewed by 6147

Abstract

Excitatory/inhibitory imbalances are implicated in many neurological disorders. Previously, we showed that chronically elevated network activity induces vulnerability in neurons due to loss of signal transducer and activator of transcription 3 (STAT3) signaling in response to the impairment of the serine/threonine kinase, extracellular-signal-regulated [...] Read more.

Excitatory/inhibitory imbalances are implicated in many neurological disorders. Previously, we showed that chronically elevated network activity induces vulnerability in neurons due to loss of signal transducer and activator of transcription 3 (STAT3) signaling in response to the impairment of the serine/threonine kinase, extracellular-signal-regulated kinases 1/2 (Erk1/2) activation. However, how phosphorylation of Erk1/2 decreases during elevated neuronal activity was unknown. Here I show the pErk1/2 decrease induced by 4-aminopyridine (4-AP), an A-type potassium channel inhibitor can be blocked by a broad-spectrum matrix-metalloproteinase (MMP) inhibitor, FN-439. Surface expression levels of integrin β1 dramatically decrease when neurons are challenged by chronically elevated activity, which is reversed by FN-439. Treatment with 4-AP induces degradation of focal adhesion kinase (FAK), the mediator of integrin signaling. As a result, interactions between FAK and growth factor receptor-bound protein 2 (Grb2), the adaptor protein that mediates Erk1/2 activation by integrin, are severely impaired. Together, these data suggest the loss of integrin signaling during elevated activity causes vulnerability in neurons. Full article

(This article belongs to the Special Issue Mechanisms of Neurodegeneration)

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Review

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Genetic and Transcriptomic Profiles of Inflammation in Neurodegenerative Diseases: Alzheimer, Parkinson, Creutzfeldt-Jakob and Tauopathies

by Irene López González, Paula Garcia-Esparcia, Franc Llorens and Isidre Ferrer

Int. J. Mol. Sci. 2016, 17(2), 206; https://doi.org/10.3390/ijms17020206 - 4 Feb 2016

Cited by 82 | Viewed by 8683

Abstract

Polymorphisms in certain inflammatory-related genes have been identified as putative differential risk factors of neurodegenerative diseases with abnormal protein aggregates, such as sporadic Alzheimer’s disease (AD) and sporadic Parkinson’s disease (sPD). Gene expression studies of cytokines and mediators of the immune response have [...] Read more.

Polymorphisms in certain inflammatory-related genes have been identified as putative differential risk factors of neurodegenerative diseases with abnormal protein aggregates, such as sporadic Alzheimer’s disease (AD) and sporadic Parkinson’s disease (sPD). Gene expression studies of cytokines and mediators of the immune response have been made in post-mortem human brain samples in AD, sPD, sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2, Pick’s disease (PiD), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration linked to mutation P301L in MAPT Frontotemporal lobar degeneration-tau (FTLD-tau). The studies have disclosed variable gene regulation which is: (1) disease-dependent in the frontal cortex area 8 in AD, sPD, sCJD MM1 and VV2, PiD, PSP and FTLD-tau; (2) region-dependent as seen when comparing the entorhinal cortex, orbitofrontal cortex, and frontal cortex area 8 (FC) in AD; the substantia nigra, putamen, FC, and angular gyrus in PD, as well as the FC and cerebellum in sCJD; (3) genotype-dependent as seen considering sCJD MM1 and VV2; and (4) stage-dependent as seen in AD at different stages of disease progression. These observations show that regulation of inflammation is much more complicated and diverse than currently understood, and that new therapeutic approaches must be designed in order to selectively act on specific targets in particular diseases and at different time points of disease progression. Full article

(This article belongs to the Special Issue Mechanisms of Neurodegeneration)

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Molecular Pathological Classification of Neurodegenerative Diseases: Turning towards Precision Medicine

by Gabor G. Kovacs

Int. J. Mol. Sci. 2016, 17(2), 189; https://doi.org/10.3390/ijms17020189 - 2 Feb 2016

Cited by 230 | Viewed by 18401

Abstract

Neurodegenerative diseases (NDDs) are characterized by selective dysfunction and loss of neurons associated with pathologically altered proteins that deposit in the human brain but also in peripheral organs. These proteins and their biochemical modifications can be potentially targeted for therapy or used as [...] Read more.

Neurodegenerative diseases (NDDs) are characterized by selective dysfunction and loss of neurons associated with pathologically altered proteins that deposit in the human brain but also in peripheral organs. These proteins and their biochemical modifications can be potentially targeted for therapy or used as biomarkers. Despite a plethora of modifications demonstrated for different neurodegeneration-related proteins, such as amyloid-β, prion protein, tau, α-synuclein, TAR DNA-binding protein 43 (TDP-43), or fused in sarcoma protein (FUS), molecular classification of NDDs relies on detailed morphological evaluation of protein deposits, their distribution in the brain, and their correlation to clinical symptoms together with specific genetic alterations. A further facet of the neuropathology-based classification is the fact that many protein deposits show a hierarchical involvement of brain regions. This has been shown for Alzheimer and Parkinson disease and some forms of tauopathies and TDP-43 proteinopathies. The present paper aims to summarize current molecular classification of NDDs, focusing on the most relevant biochemical and morphological aspects. Since the combination of proteinopathies is frequent, definition of novel clusters of patients with NDDs needs to be considered in the era of precision medicine. Optimally, neuropathological categorizing of NDDs should be translated into in vivo detectable biomarkers to support better prediction of prognosis and stratification of patients for therapy trials. Full article

(This article belongs to the Special Issue Mechanisms of Neurodegeneration)

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Microglia-Mediated Neuroinflammation and Neurotrophic Factor-Induced Protection in the MPTP Mouse Model of Parkinson’s Disease-Lessons from Transgenic Mice

by Venissa Machado, Tanja Zöller, Abdelraheim Attaai and Björn Spittau

Int. J. Mol. Sci. 2016, 17(2), 151; https://doi.org/10.3390/ijms17020151 - 26 Jan 2016

Cited by 61 | Viewed by 10739

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease characterised by histopathological and biochemical manifestations such as loss of midbrain dopaminergic (DA) neurons and decrease in dopamine levels accompanied by a concomitant neuroinflammatory response in the affected brain regions. Over the past decades, the use [...] Read more.

Parkinson’s disease (PD) is a neurodegenerative disease characterised by histopathological and biochemical manifestations such as loss of midbrain dopaminergic (DA) neurons and decrease in dopamine levels accompanied by a concomitant neuroinflammatory response in the affected brain regions. Over the past decades, the use of toxin-based animal models has been crucial to elucidate disease pathophysiology, and to develop therapeutic approaches aimed to alleviate its motor symptoms. Analyses of transgenic mice deficient for cytokines, chemokine as well as neurotrophic factors and their respective receptors in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD have broadened the current knowledge of neuroinflammation and neurotrophic support. Here, we provide a comprehensive review that summarises the contribution of microglia-mediated neuroinflammation in MPTP-induced neurodegeneration. Moreover, we highlight the contribution of neurotrophic factors as endogenous and/or exogenous molecules to slow the progression of midbrain dopaminergic (mDA) neurons and further discuss the potential of combined therapeutic approaches employing neuroinflammation modifying agents and neurotrophic factors. Full article

(This article belongs to the Special Issue Mechanisms of Neurodegeneration)

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Insights into Mechanisms of Chronic Neurodegeneration

by Abigail B. Diack, James D. Alibhai, Rona Barron, Barry Bradford, Pedro Piccardo and Jean C. Manson

Int. J. Mol. Sci. 2016, 17(1), 82; https://doi.org/10.3390/ijms17010082 - 12 Jan 2016

Cited by 33 | Viewed by 7141

Abstract

Chronic neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and prion diseases are characterised by the accumulation of abnormal conformers of a host encoded protein in the central nervous system. The process leading to neurodegeneration is still poorly defined and thus [...] Read more.

Chronic neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and prion diseases are characterised by the accumulation of abnormal conformers of a host encoded protein in the central nervous system. The process leading to neurodegeneration is still poorly defined and thus development of early intervention strategies is challenging. Unique amongst these diseases are Transmissible Spongiform Encephalopathies (TSEs) or prion diseases, which have the ability to transmit between individuals. The infectious nature of these diseases has permitted in vivo and in vitro modelling of the time course of the disease process in a highly reproducible manner, thus early events can be defined. Recent evidence has demonstrated that the cell-to-cell spread of protein aggregates by a “prion-like mechanism” is common among the protein misfolding diseases. Thus, the TSE models may provide insights into disease mechanisms and testable hypotheses for disease intervention, applicable to a number of these chronic neurodegenerative diseases. Full article

(This article belongs to the Special Issue Mechanisms of Neurodegeneration)

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Targeting New Candidate Genes by Small Molecules Approaching Neurodegenerative Diseases

by Hueng-Chuen Fan, Ching-Shiang Chi, Shin-Nan Cheng, Hsiu-Fen Lee, Jeng-Dau Tsai, Shinn-Zong Lin and Horng-Jyh Harn

Int. J. Mol. Sci. 2016, 17(1), 26; https://doi.org/10.3390/ijms17010026 - 25 Dec 2015

Cited by 22 | Viewed by 6943

Abstract

Neurodegenerative diseases (NDs) are among the most feared of the disorders that afflict humankind for the lack of specific diagnostic tests and effective treatments. Understanding the molecular, cellular, biochemical changes of NDs may hold therapeutic promise against debilitating central nerve system (CNS) disorders. [...] Read more.

Neurodegenerative diseases (NDs) are among the most feared of the disorders that afflict humankind for the lack of specific diagnostic tests and effective treatments. Understanding the molecular, cellular, biochemical changes of NDs may hold therapeutic promise against debilitating central nerve system (CNS) disorders. In the present review, we summarized the clinical presentations and biology backgrounds of NDs, including Parkinson’s disease (PD), Huntington’s disease (HD), and Alzheimer’s disease (AD) and explored the role of molecular mechanisms, including dys-regulation of epigenetic control mechanisms, Ataxia-telangiectasia-mutated protein kinase (ATM), and neuroinflammation in the pathogenesis of NDs. Targeting these mechanisms may hold therapeutic promise against these devastating diseases. Full article

(This article belongs to the Special Issue Mechanisms of Neurodegeneration)

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Bioinformatics Mining and Modeling Methods for the Identification of Disease Mechanisms in Neurodegenerative Disorders

by Martin Hofmann-Apitius, Gordon Ball, Stephan Gebel, Shweta Bagewadi, Bernard De Bono, Reinhard Schneider, Matt Page, Alpha Tom Kodamullil, Erfan Younesi, Christian Ebeling, Jesper Tegnér and Luc Canard

Int. J. Mol. Sci. 2015, 16(12), 29179-29206; https://doi.org/10.3390/ijms161226148 - 7 Dec 2015

Cited by 44 | Viewed by 10612

Abstract

Since the decoding of the Human Genome, techniques from bioinformatics, statistics, and machine learning have been instrumental in uncovering patterns in increasing amounts and types of different data produced by technical profiling technologies applied to clinical samples, animal models, and cellular systems. Yet, [...] Read more.

Since the decoding of the Human Genome, techniques from bioinformatics, statistics, and machine learning have been instrumental in uncovering patterns in increasing amounts and types of different data produced by technical profiling technologies applied to clinical samples, animal models, and cellular systems. Yet, progress on unravelling biological mechanisms, causally driving diseases, has been limited, in part due to the inherent complexity of biological systems. Whereas we have witnessed progress in the areas of cancer, cardiovascular and metabolic diseases, the area of neurodegenerative diseases has proved to be very challenging. This is in part because the aetiology of neurodegenerative diseases such as Alzheimer´s disease or Parkinson´s disease is unknown, rendering it very difficult to discern early causal events. Here we describe a panel of bioinformatics and modeling approaches that have recently been developed to identify candidate mechanisms of neurodegenerative diseases based on publicly available data and knowledge. We identify two complementary strategies—data mining techniques using genetic data as a starting point to be further enriched using other data-types, or alternatively to encode prior knowledge about disease mechanisms in a model based framework supporting reasoning and enrichment analysis. Our review illustrates the challenges entailed in integrating heterogeneous, multiscale and multimodal information in the area of neurology in general and neurodegeneration in particular. We conclude, that progress would be accelerated by increasing efforts on performing systematic collection of multiple data-types over time from each individual suffering from neurodegenerative disease. The work presented here has been driven by project AETIONOMY; a project funded in the course of the Innovative Medicines Initiative (IMI); which is a public-private partnership of the European Federation of Pharmaceutical Industry Associations (EFPIA) and the European Commission (EC). Full article

(This article belongs to the Special Issue Mechanisms of Neurodegeneration)

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The Function of Autophagy in Neurodegenerative Diseases

by Yoshimitsu Kiriyama and Hiromi Nochi

Int. J. Mol. Sci. 2015, 16(11), 26797-26812; https://doi.org/10.3390/ijms161125990 - 9 Nov 2015

Cited by 128 | Viewed by 14090

Abstract

Macroautophagy, hereafter referred to as autophagy, is a bulk degradation process performed by lysosomes in which aggregated and altered proteins as well as dysfunctional organelles are decomposed. Autophagy is a basic cellular process that maintains homeostasis and is crucial for postmitotic neurons. Thus, [...] Read more.

Macroautophagy, hereafter referred to as autophagy, is a bulk degradation process performed by lysosomes in which aggregated and altered proteins as well as dysfunctional organelles are decomposed. Autophagy is a basic cellular process that maintains homeostasis and is crucial for postmitotic neurons. Thus, impaired autophagic processes in neurons lead to improper homeostasis and neurodegeneration. Recent studies have suggested that impairments of the autophagic process are associated with several neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and static encephalopathy of childhood with neurodegeneration in adulthood. In this review, we focus on the recent findings regarding the autophagic process and the involvement of autophagy in neurodegenerative diseases. Full article

(This article belongs to the Special Issue Mechanisms of Neurodegeneration)

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Alzheimer’s Disease: Mechanism and Approach to Cell Therapy

by Takashi Amemori, Pavla Jendelova, Jiri Ruzicka, Lucia Machova Urdzikova and Eva Sykova

Int. J. Mol. Sci. 2015, 16(11), 26417-26451; https://doi.org/10.3390/ijms161125961 - 4 Nov 2015

Cited by 83 | Viewed by 15301

Abstract

Alzheimer’s disease (AD) is the most common form of dementia. The risk of AD increases with age. Although two of the main pathological features of AD, amyloid plaques and neurofibrillary tangles, were already recognized by Alois Alzheimer at the beginning of the 20th [...] Read more.

Alzheimer’s disease (AD) is the most common form of dementia. The risk of AD increases with age. Although two of the main pathological features of AD, amyloid plaques and neurofibrillary tangles, were already recognized by Alois Alzheimer at the beginning of the 20th century, the pathogenesis of the disease remains unsettled. Therapeutic approaches targeting plaques or tangles have not yet resulted in satisfactory improvements in AD treatment. This may, in part, be due to early-onset and late-onset AD pathogenesis being underpinned by different mechanisms. Most animal models of AD are generated from gene mutations involved in early onset familial AD, accounting for only 1% of all cases, which may consequently complicate our understanding of AD mechanisms. In this article, the authors discuss the pathogenesis of AD according to the two main neuropathologies, including senescence-related mechanisms and possible treatments using stem cells, namely mesenchymal and neural stem cells. Full article

(This article belongs to the Special Issue Mechanisms of Neurodegeneration)

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Genetics Underlying Atypical Parkinsonism and Related Neurodegenerative Disorders

by Sonja W. Scholz and Jose Bras

Int. J. Mol. Sci. 2015, 16(10), 24629-24655; https://doi.org/10.3390/ijms161024629 - 16 Oct 2015

Cited by 19 | Viewed by 19100

Abstract

Atypical parkinsonism syndromes, such as dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration, are neurodegenerative diseases with complex clinical and pathological features. Heterogeneity in clinical presentations, possible secondary determinants as well as mimic syndromes pose a major challenge [...] Read more.

Atypical parkinsonism syndromes, such as dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration, are neurodegenerative diseases with complex clinical and pathological features. Heterogeneity in clinical presentations, possible secondary determinants as well as mimic syndromes pose a major challenge to accurately diagnose patients suffering from these devastating conditions. Over the last two decades, significant advancements in genomic technologies have provided us with increasing insights into the molecular pathogenesis of atypical parkinsonism and their intriguing relationships to related neurodegenerative diseases, fueling new hopes to incorporate molecular knowledge into our diagnostic, prognostic and therapeutic approaches towards managing these conditions. In this review article, we summarize the current understanding of genetic mechanisms implicated in atypical parkinsonism syndromes. We further highlight mimic syndromes relevant to differential considerations and possible future directions. Full article

(This article belongs to the Special Issue Mechanisms of Neurodegeneration)

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Genetic Polymorphisms of Glutathione-Related Enzymes (GSTM1, GSTT1, and GSTP1) and Schizophrenia Risk: A Meta-Analysis

by Su Kang Kim, Sang Wook Kang, Joo-Ho Chung, Hae Jeong Park, Kyu Bong Cho and Min-Su Park

Int. J. Mol. Sci. 2015, 16(8), 19602-19611; https://doi.org/10.3390/ijms160819602 - 19 Aug 2015

Cited by 26 | Viewed by 5858

Abstract

The association between polymorphisms of glutathione-related enzyme (GST) genes and the risk of schizophrenia has been investigated in many published studies. However, their results were inconclusive. Therefore, we performed a meta-analysis to explore the association between the GSTM1, GSTT1, and GSTP1 [...] Read more.

The association between polymorphisms of glutathione-related enzyme (GST) genes and the risk of schizophrenia has been investigated in many published studies. However, their results were inconclusive. Therefore, we performed a meta-analysis to explore the association between the GSTM1, GSTT1, and GSTP1 polymorphisms and the risk of schizophrenia. Twelve case-control studies were included in this meta-analysis. The odds ratio (OR) and 95% confidence interval (95% CI) were used to investigate the strength of the association. Our meta-analysis results revealed that GSTM1, GSTT1, and GSTP1 polymorphisms were not related to risk of schizophrenia (p > 0.05 in each model). Further analyses based on ethnicity, GSTM polymorphism showed weak association with schizophrenia in East Asian population (OR = 1.314, 95% CI = 1.025–1.684, p = 0.031). In conclusion, our meta-analysis indicated the GSTM1 polymorphism may be the only genetic risk factor for schizophrenia in East Asian population. However, more meta-analysis with a larger sample size were needed to provide more precise evidence. Full article

(This article belongs to the Special Issue Mechanisms of Neurodegeneration)

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