RNA/DNA Binding Protein TDP43 Regulates DNA Mismatch Repair Genes with Implications for Genome Stability.

TDP43 is an RNA/DNA binding protein increasingly recognized for its role in neurodegenerative conditions including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As characterized by its aberrant nuclear export and cytoplasmic aggregation, TDP43 proteinopathy is a hallmark feature in over 95% of ALS/FTD cases, leading to the formation of detrimental cytosolic aggregates and a reduction in nuclear functionality within neurons. Building on our prior work linking TDP43 proteinopathy to the accumulation of DNA double-strand breaks (DSBs) in neurons, the present investigation uncovers a novel regulatory relationship between TDP43 and DNA mismatch repair (MMR) gene expressions. Here, we show that TDP43 depletion or overexpression directly affects the expression of key MMR genes. Alterations include MLH1, MSH2, MSH3, MSH6, and PMS2 levels across various primary cell lines, independent of their proliferative status. Our results specifically establish that TDP43 selectively influences the expression of MLH1 and MSH6 by influencing their alternative transcript splicing patterns and stability. We furthermore find aberrant MMR gene expression is linked to TDP43 proteinopathy in two distinct ALS mouse models and post-mortem brain and spinal cord tissues of ALS patients. Notably, MMR depletion resulted in the partial rescue of TDP43 proteinopathy-induced DNA damage and signaling. Moreover, bioinformatics analysis of the TCGA cancer database reveals significant associations between TDP43 expression, MMR gene expression, and mutational burden across multiple cancers. Collectively, our findings implicate TDP43 as a critical regulator of the MMR pathway and unveil its broad impact on the etiology of both neurodegenerative and neoplastic pathologies.

Mitochondria-Targeted Oligomeric α-Synuclein Induces TOM40 Degradation and Mitochondrial Dysfunction in Parkinson's Disease and Parkinsonism-Dementia of Guam.

Mitochondrial dysfunction is a central aspect of Parkinson's disease (PD) pathology, yet the underlying mechanisms are not fully understood. This study investigates the link between α-Synuclein (α-Syn) pathology and the loss of translocase of the outer mitochondrial membrane 40 (TOM40), unraveling its implications for mitochondrial dysfunctions in neurons. We discovered that TOM40 protein depletion occurs in the brains of patients with Guam Parkinsonism Dementia (Guam PD) and cultured neurons expressing α-Syn proteinopathy, notably, without corresponding changes in TOM40 mRNA levels. Cultured neurons expressing α-Syn mutants, with or without a mitochondria-targeting signal (MTS) underscore the role of α-Syn's mitochondrial localization in inducing TOM40 degradation. Parkinson's Disease related etiological factors, such as 6-hydroxy dopamine or ROS/metal ions stress, which promote α-Syn oligomerization, exacerbate TOM40 depletion in PD patient-derived cells with SNCA gene triplication. Although α-Syn interacts with both TOM40 and TOM20 in the outer mitochondrial membrane, degradation is selective for TOM40, which occurs via the ubiquitin-proteasome system (UPS) pathway. Our comprehensive analyses using Seahorse technology, mitochondrial DNA sequencing, and damage assessments, demonstrate that mutant α-Syn-induced TOM40 loss results in mitochondrial dysfunction, characterized by reduced membrane potential, accumulation of mtDNA damage, deletion/insertion mutations, and altered oxygen consumption rates. Notably, ectopic supplementation of TOM40 or reducing pathological forms of α-Syn using ADP-ribosylation inhibitors ameliorate these mitochondrial defects, suggesting potential therapeutic avenues. In conclusion, our findings provide crucial mechanistic insights into how α-Syn accumulation leads to TOM40 degradation and mitochondrial dysfunction, offering insights for targeted interventions to alleviate mitochondrial defects in PD.

Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence.

TDP-43 mislocalization and aggregation are key pathological features of motor neuron diseases (MND) including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, transgenic hTDP-43 WT or ΔNLS-overexpression animal models mainly capture late-stages TDP-43 proteinopathy, and do not provide a complete understanding of early motor neuron-specific pathology during pre-symptomatic phases. We have now addressed this shortcoming by generating a new endogenous knock-in (KI) mouse model using a combination of CRISPR/Cas9 and FLEX Cre-switch strategy for the conditional expression of a mislocalized Tdp-43ΔNLS variant of mouse Tdp-43. This variant is either expressed conditionally in whole mice or specifically in the motor neurons. The mice exhibit loss of nuclear Tdp-43 concomitant with its cytosolic accumulation and aggregation in targeted cells, leading to increased DNA double-strand breaks (DSBs), signs of inflammation and DNA damage-associated cellular senescence. Notably, unlike WT Tdp43 which functionally interacts with Xrcc4 and DNA Ligase 4, the key DSB repair proteins in the non-homologous end-joining (NHEJ) pathway, the Tdp-43ΔNLS mutant sequesters them into cytosolic aggregates, exacerbating neuronal damage in mice brain. The mutant mice also exhibit myogenic degeneration in limb muscles and distinct motor deficits, consistent with the characteristics of MND. Our findings reveal progressive degenerative mechanisms in motor neurons expressing endogenous Tdp-43ΔNLS mutant, independent of TDP-43 overexpression or other confounding etiological factors. Thus, this unique Tdp-43 KI mouse model, which displays key molecular and phenotypic features of Tdp-43 proteinopathy, offers a significant opportunity to further characterize the early-stage progression of MND and also opens avenues for developing DNA repair-targeted approaches for treating TDP-43 pathology-linked neurodegenerative diseases.

Misfolded alpha-synuclein in amyotrophic lateral sclerosis: Implications for diagnosis and treatment.

BACKGROUND: Alpha-synuclein (α-Syn) oligomers and fibrils have been shown to augment the aggregation of TAR DNA-binding Protein 43 (TDP-43) monomers in vitro, supporting the idea that TDP-43 proteinopathies such as ALS may be modulated by the presence of toxic forms of α-Syn. Recently, parkinsonian features were reported in a study of European patients and Lewy bodies have been demonstrated pathologically in a similar series of patients. Based on these and other considerations, we sought to determine whether seed-competent α-Syn can be identified in spinal fluid of patients with ALS including familial, sporadic, and Guamanian forms of the disease. METHODS: Based on the finding that α-Syn has been found to be a prion-like protein, we have utilized a validated α-Synuclein seed amplification assay to determine if seed-competent α-Syn could be detected in the spinal fluid of patients with ALS. RESULTS: Toxic species of α-Syn were detected in CSF in 18 of 127 ALS patients, 5 of whom were from Guam. Two out of twenty six samples from patients with C9orf72 variant ALS had positive seed-amplification assays (SAAs). No positive tests were noted in superoxide dismutase type 1 ALS subjects (n = 14). The SAA was negative in 31 control subjects. CONCLUSIONS: Our findings suggest that a sub-group of ALS occurs in which self-replicating α-Syn is detectable and likely contributes to its pathogenesis. This finding may have implications for the diagnosis and treatment of this disorder.

Cat Ownership and Rural Residence Are Associated with Lyme Disease Prevalence in the Northeastern United States.

Lyme disease (LD) is the most common vector-borne disease in the USA. Beyond its tick-borne nature, however, risk factors for LD are poorly understood. We used an online questionnaire to compare LD patients and non-LD counterparts and elucidate factors associated with LD. We investigated demographic, lifestyle, and household characteristics and use of prevention measures. Associations with LD were modeled using logistic regression, and average marginal effects were estimated. In total, 185 active or past LD patients and 139 non-patients participated. The majority of respondents were white (95%) and female (65%). Controlling for age, sex, and type of residential area, pet ownership was associated with an 11.1% (p = 0.038) increase in the probability of LD. This effect was limited to cat owners (OR: 2.143, p = 0.007; dog owners, OR: 1.398, p = 0.221). Living in rural areas was associated with a 36% (p = 0.001) increase in the probability of LD compared to living in an urban area. Participants who reported knowing someone with Lyme Disease were more likely to wear insect repellant and perform tick checks. This study suggests opportunities for improved LD prevention, including advising cat owners of their increased risk. Although patterns in adoption of LD prevention methods remain poorly understood, concern about LD risk does motivate their use.

Recent kuru-induced female gene flow disrupted the coevolution of genes and languages in the Papua New Guinea highlands.

OBJECTIVES: The island of New Guinea was settled by modern human over 50,000 years ago, and is currently characterized by a complex landscape and contains one-seventh of the world's languages. The Eastern Highlands of New Guinea were also the home to the devastating prion disease called kuru that primarily affected Fore-speaking populations, with some 68% of cases involving adult females. We characterized the mitochondrial DNA (mtDNA) diversity of highlanders from Papua New Guinea (PNG) to: (a) gain insight into the coevolution of genes and languages in situ over mountainous landscapes; and (b) evaluate the recent influence of kuru mortality on the pattern of female gene flow. MATERIALS AND METHODS: We sequenced the mtDNA hypervariable segment 1 of 870 individuals from the Eastern and Southern Highlands of PNG using serums collected in the 1950s to 1960s. These highlanders were selected from villages representing 15 linguistic groups within the Trans-New Guinea phylum. Genetic, linguistic, and geographic distances were calculated separately and correlations among those distance matrices were assessed using the Mantel test. RESULTS: Geographic, genetic, and linguistic patterns were independently correlated with each other (p < .05). Increased mtDNA diversity in kuru-affected populations and low Fst estimates between kuru-affected linguistic groups were observed. DISCUSSION: In general, the genetic structure among the Highland populations was shaped by both geography and language, and language is a good predictor of mtDNA affinity in the PNG Highlands. High kuru female mortality increased female gene flow locally, disrupting coevolutionary pattern among genes, languages, and geography.

Activation of the Unfolded Protein Response and Proteostasis Disturbance in Parkinsonism-Dementia of Guam.

Guam parkinsonism-dementia (G-PD) is a progressive and fatal neurodegenerative disorder among the native inhabitants of the Mariana Islands that manifests clinically with parkinsonism as well as dementia. Neuropathologically, G-PD is characterized by abundant neurofibrillary tangles composed of hyperphosphorylated tau, marked deposition of transactive response DNA-binding protein 43 kDa (TDP-43), and neuronal loss. The mechanisms that underlie neurodegeneration in G-PD are poorly understood. Here, we report that the unfolded protein response (UPR) is activated in G-PD brains. Specifically, we show that the endoplasmic reticulum (ER) chaperone binding immunoglobulin protein/glucose-regulated protein 78 kDa and phosphorylated (activated) ER stress sensor protein kinase RNA-like ER kinase accumulate in G-PD brains. Furthermore, proteinaceous aggregates in G-PD brains are found to contain several proteins related to the ubiquitin-proteasome system (UPS) and the autophagy pathway, two major mechanisms for intracellular protein degradation. In particular, a mutant ubiquitin (UBB+1), whose presence is a marker for UPS dysfunction, is shown to accumulate in G-PD brains. We demonstrate that UBB+1 is a potent modifier of TDP-43 aggregation and cytotoxicity in vitro. Overall, these data suggest that UPR activation and intracellular proteolytic pathways are intimately connected with the accumulation of aggregated proteins in G-PD.

Risk Factors of Lyme Disease: An Intersection of Environmental Ecology and Systems Science.

Lyme disease (LD) cases have been on the rise throughout the United States, costing the healthcare system up to $1.3 billion per year, and making LD one of the greatest threats to public health. Factors influencing the number of LD cases range from environmental to system-level variables, but little is known about the influence of vegetation (canopy, understory, and ground cover) and human behavioral risk on LD cases and exposure to infected ticks. We determined the influence of various risk factors on the risk of exposure to infected ticks on 22 different walkways using multinomial logistic regression. The model classifies the walkways into high-risk and low-risk categories with 90% accuracy, in which the understory, human risk, and number of rodents are significant indicators. These factors should be managed to control the risk of transmission of LD to humans.

Using multiple correspondence analysis to identify behaviour patterns associated with overweight and obesity in Vanuatu adults.

OBJECTIVE: The present study evaluates the use of multiple correspondence analysis (MCA), a type of exploratory factor analysis designed to reduce the dimensionality of large categorical data sets, in identifying behaviours associated with measures of overweight/obesity in Vanuatu, a rapidly modernizing Pacific Island country. DESIGN: Starting with seventy-three true/false questions regarding a variety of behaviours, MCA identified twelve most significantly associated with modernization status and transformed the aggregate binary responses of participants to these twelve questions into a linear scale. Using this scale, individuals were separated into three modernization groups (tertiles) among which measures of body fat were compared and OR for overweight/obesity were computed. SETTING: Vanuatu.ParticipantsNi-Vanuatu adults (n 810) aged 20-85 years. RESULTS: Among individuals in the tertile characterized by positive responses to most of or all the twelve modernization questions, weight and measures of body fat and the likelihood that measures of body fat were above the US 75th percentile were significantly greater compared with individuals in the tertiles characterized by mostly or partly negative responses. CONCLUSIONS: The study indicates that MCA can be used to identify individuals or groups at risk for overweight/obesity, based on answers to simply-put questions. MCA therefore may be useful in areas where obtaining detailed information about modernization status is constrained by time, money or manpower.

Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects.

Genome damage and their defective repair have been etiologically linked to degenerating neurons in many subtypes of amyotrophic lateral sclerosis (ALS) patients; however, the specific mechanisms remain enigmatic. The majority of sporadic ALS patients feature abnormalities in the transactivation response DNA-binding protein of 43 kDa (TDP-43), whose nucleo-cytoplasmic mislocalization is characteristically observed in spinal motor neurons. While emerging evidence suggests involvement of other RNA/DNA binding proteins, like FUS in DNA damage response (DDR), the role of TDP-43 in DDR has not been investigated. Here, we report that TDP-43 is a critical component of the nonhomologous end joining (NHEJ)-mediated DNA double-strand break (DSB) repair pathway. TDP-43 is rapidly recruited at DSB sites to stably interact with DDR and NHEJ factors, specifically acting as a scaffold for the recruitment of break-sealing XRCC4-DNA ligase 4 complex at DSB sites in induced pluripotent stem cell-derived motor neurons. shRNA or CRISPR/Cas9-mediated conditional depletion of TDP-43 markedly increases accumulation of genomic DSBs by impairing NHEJ repair, and thereby, sensitizing neurons to DSB stress. Finally, TDP-43 pathology strongly correlates with DSB repair defects, and damage accumulation in the neuronal genomes of sporadic ALS patients and in Caenorhabditis elegans mutant with TDP-1 loss-of-function. Our findings thus link TDP-43 pathology to impaired DSB repair and persistent DDR signaling in motor neuron disease, and suggest that DSB repair-targeted therapies may ameliorate TDP-43 toxicity-induced genome instability in motor neuron disease.

Coming to grips with economic development: Variation in adult hand grip strength during health transition in Vanuatu.

OBJECTIVES: To determine whether (1) maximal handgrip strength (HGS) is associated with inter-island level of economic development in Vanuatu, (2) how associations between island of residence and HGS are mediated by age, sex, body size/composition, and individual sociodeomographic variation, and (3) whether HGS is predictive of hypertension. MATERIAL AND METHODS: HGS was collected from 833 adult (aged 18 and older) men and women on five islands representing a continuum of economic development in Vanuatu. HGS was measured using a handheld dynamometer. Participants were administered in an extensive sociobehavioral questionnaire and were also assessed for height, weight, percent body fat, forearm skinfold thickness, forearm circumference, and blood pressure. RESULTS: HGS was significantly greater in men than in women regardless of island of residence. HGS was also significantly positively associated with inter-island level of economic development. Grip strength-to-weight ratio was not different across islands except in older individuals, where age-related decline occurred primarily on islands with greater economic development. HGS significantly declined with age in both men and women. CONCLUSION: HGS is positively associated with modernization in Vanuatu, but the relationship between HGS and modernization is largely due to an association of both variables with increased body size on more modernized islands. Further research on the role of individual variation in diet and physical activity are necessary to clarify the relationship between HGS and modernization.

Lyme Disease Transmission Risk: Seasonal Variation in the Built Environment.

Seasonal variation in spatial distribution and pathogen prevalence of Borrelia burgdorferi in blacklegged ticks (Ixodes scapularis) influences human population risk of Lyme disease in peri-urban built environments. Parks, gardens, playgrounds, school campuses and neighborhoods represent a significant risk for Lyme disease transmission. From June 2012 through May 2014, ticks were collected using 1 m² corduroy cloths dragged over low-lying vegetation parallel to walkways with high human foot traffic. DNA was extracted from ticks, purified and presence of B. burgdorferi assessed by polymerase chain reaction amplification. Summer is reported as the time of highest risk for Lyme disease transmission in the United States and our results indicate a higher tick density of 26.0/1000 m² in summer vs. 0.2/1000 m² to 10.5/1000 m² in spring and fall. However, our findings suggest that tick infection rate is proportionally higher during the fall and spring than summer (30.0⁻54.7% in fall and 36.8⁻65.6% in spring vs. 20.0⁻28.2% in summer). Seasonal variation in infected tick density has significant implications for Lyme disease transmission as people are less likely to be aware of ticks in built environments, and unaware of increased infection in ticks in spring and fall. These factors may lead to more tick bites resulting in Lyme infection.

Cerebrovascular inflammation is associated with tau pathology in Guam parkinsonism dementia.

Parkinsonism-dementia complex of Guam (Guam PDC) is a neurodegenerative disease with parkinsonism and early onset Alzheimer-like dementia. Guam PDC belongs to the family of neurodegenerative disorders, known as tauopathies, which are histopathologically characterized by abnormal deposition of microtubule-associated protein tau. While changes in the blood-brain barrier (BBB) in Alzheimer's disease are increasingly recognized, dysfunction of BBB in Guam PDC has not been extensively studied. In this study, we characterized cerebrovascular changes in the patients with Guam PDC. The brain tissue from ten post-mortem Guam PDC patients and six non-demented controls were assessed for structural and functional changes in BBB. Entorhinal cortex sections were immunostained for the markers of brain endothelial cells (claudin-5, occludin, and collagen IV) and inflammation (VCAM-1, ICAM-1, P-Selectin, and E-Selectin). The ultrastructure of brain capillaries was investigated by confocal microscopy and morphological changes and intensity alterations were evaluated. We found a significant decrease of tight junction proteins and the upregulation of adhesion molecules that correlated with the presence of neurofibrillary tangles. In addition, we showed the presence of CD3+-positive cells in the brain areas affected by pathological lesions. Our findings indicate that pathological lesions in Guam PDC are associated with inflammatory changes of brain capillaries and could mediate transmigration of cells to the brain parenchyma.

A novel liquid chromatography/mass spectrometry method for determination of neurotransmitters in brain tissue: Application to human tauopathies.

Neurotransmitters, small molecules widely distributed in the central nervous system are essential in transmitting electrical signals across neurons via chemical communication. Dysregulation of these chemical signaling molecules is linked to numerous neurological diseases including tauopathies. In this study, a precise and reliable liquid chromatography method was established with tandem mass spectrometry detection for the simultaneous determination of aspartic acid, asparagine, glutamic acid, glutamine, γ-aminobutyric acid, N-acetyl-l-aspartic acid, pyroglutamic acid, acetylcholine and choline in human brain tissue. The method was successfully applied to the analysis of human brain tissues from three different tauopathies; corticobasal degeneration, progressive supranuclear palsy and parkinsonism-dementia complex of Guam. Neurotransmitters were analyzed on ultra-high performance chromatography (UHPLC) using an ethylene bridged hybrid amide column coupled with tandem mass spectrometry (MS/MS). Identification and quantification of neurotransmitters was carried out by ESI+ mass spectrometry detection. We optimized sample preparation to achieve simple and fast extraction of all nine analytes. Our method exhibited an excellent linearity for all analytes (all coefficients of determination >0.99), with inter-day and intra-day precision yielding relative standard deviations 3.2%-11.2% and an accuracy was in range of 92.6%-104.3%. The present study, using the above method, is the first to demonstrate significant alterations of brain neurotransmitters caused by pathological processes in the brain tissues of patient with three different tauopathies.

Secular change in adult stature associated with modernization in Vanuatu.

OBJECTIVE: To determine whether: (1) there is a secular increase in adult stature in Vanuatu, and (2) whether adult stature is positively associated with modernization in Vanuatu. METHODS: This study reports on stature measurements collected on 650 adult (age > 17 years) men and women from four islands of varying economic development in Vanuatu. Measurements were collected as part of the Vanuatu Health Transitions Research Project in 2007 and 2011. RESULTS: Stature increased significantly in adults born between the 1940s and 1960s in Vanuatu, before leveling off in those born between the 1970s and 1990s. Adults are significantly taller on Efate, the most modernized island in the study sample, than on the less economically developed islands. CONCLUSIONS: Modernization is likely associated with improvements in child growth in Vanuatu, as assessed by gains in adult stature.

Rolling Tobacco in Banana Leaves, Newspaper, or Copybook Paper Associated With Significant Reduction in Lung Function in Vanuatu.

In addition to the widespread availability of packaged cigarettes, the inhabitants of island nations of the Southwest Pacific frequently smoke commercially available loose tobacco using manufactured rolling papers, as well as locally grown tobacco rolled in manufactured rolling paper or wrapped in leaves, copybook paper, and newspaper. In this study, Vanuatu men who smoked local tobacco rolled in leaves, copybook paper, or newspaper showed significantly lower forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and FEV1/FVC ratios than men who smoked packaged cigarettes, store-bought tobacco rolled in manufactured rolling paper, or who smoked locally grown tobacco rolled in manufactured rolling papers. The addition of toxins from these unusual tobacco-wrapping media produces lung function deficits similar to the pattern noted among tobacco smokers who also inhale smoke from burning biomass. Thus, public health initiatives should consider including strategies addressing the use of wrapping media among smokers in South Pacific island societies.

Serological evidence for transmission of multiple dengue virus serotypes in Papua New Guinea and West Papua prior to 1963.

Little is known about the natural history of dengue in Papua New Guinea (PNG). We assessed dengue virus (DENV)-specific neutralizing antibody profiles in serum samples collected from northern and southern coastal areas and the highland region of New Guinea between 1959 and 1963. Neutralizing antibodies were demonstrated in sera from the northern coast of New Guinea: from Sabron in Dutch New Guinea (now known as West Papua) and from four villages in East Sepik in what is now PNG. Previous monotypic infection with DENV-1, DENV-2, and DENV-4 was identified, with a predominance of anti-DENV-2 neutralizing antibody. The majority of positive sera demonstrated evidence of multiple previous DENV infections and neutralizing activity against all four serotypes was detected, with anti-DENV-2 responses being most frequent and of greatest magnitude. No evidence of previous DENV infection was identified in the Asmat villages of the southern coast and a single anti-DENV-positive sample was identified in the Eastern Highlands of PNG. These findings indicate that multiple DENV serotypes circulated along the northern coast of New Guinea at different times in the decades prior to 1963 and support the notion that dengue has been a significant yet neglected tropical infection in PNG for many decades.

Ownership of consumer electronics is associated with measures of adiposity during health transition in Vanuatu.

OBJECTIVE: The Republic of Vanuatu, like many developing nations, is undergoing a rapid health transition. Our previous study identified several behavioral risk factors for the rising prevalence of obesity. Unexpectedly, daily time spent using television and radio was revealed as a protective factor for obesity in 2007. In this study, we sought to explore associations between ownership of consumer electronics (CE) and measures of adiposity in Vanuatu in 2011. METHODS: We surveyed 873 adults from five islands varying in level of economic development. Height, weight, and waist circumferences; triceps, subscapular, and suprailiac skinfolds; and percent body fat by bioelectrical impedance were measured. Ownership of eight types of CE, diet through 24-h dietary recall and leisure-time activity patterns were assessed using a questionnaire. RESULTS: Participants from more developed islands owned more types of CE, and revealed higher measures of adiposity on average as well as higher prevalence of obesity/central obesity. When controlling for demographic factors, and dietary and activity patterns, increased measures of adiposity and risk for obesity/central obesity were associated with ownership of cellphones, music players, televisions, video players, microwaves, and/or refrigerators. Positive correlations between CE ownership and measures of adiposity were mainly observed among men on the two most developed islands. CONCLUSIONS: The results of this study indicate a possible role of CE use in the rising prevalence of obesity and the shift to a sedentary lifestyle in Vanuatu and many other modernizing regions, where prevention efforts including education on healthy use of CE are imperative.

Model-based risk assessment and public health analysis to prevent Lyme disease.

The number of Lyme disease (LD) cases in the northeastern United States has been dramatically increasing with over 300 000 new cases each year. This is due to numerous factors interacting over time including low public awareness of LD, risk behaviours and clothing choices, ecological and climatic factors, an increase in rodents within ecologically fragmented peri-urban built environments and an increase in tick density and infectivity in such environments. We have used a system dynamics (SD) approach to develop a simulation tool to evaluate the significance of risk factors in replicating historical trends of LD cases, and to investigate the influence of different interventions, such as increasing awareness, controlling clothing risk and reducing mouse populations, in reducing LD risk. The model accurately replicates historical trends of LD cases. Among several interventions tested using the simulation model, increasing public awareness most significantly reduces the number of LD cases. This model provides recommendations for LD prevention, including further educational programmes to raise awareness and control behavioural risk. This model has the potential to be used by the public health community to assess the risk of exposure to LD.

TDP-43/FUS in motor neuron disease: Complexity and challenges.

Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear. One unique feature of TDP-43 and FUS pathogenesis in ALS is their nuclear clearance and simultaneous cytoplasmic aggregation in affected motor neurons. Since the discoveries in the last decade implicating TDP-43 and FUS toxicity in ALS, a majority of studies have focused on their cytoplasmic aggregation and disruption of their RNA-binding functions. However, TDP-43 and FUS also bind to DNA, although the significance of their DNA binding in disease-affected neurons has been less investigated. A recent observation of accumulated genomic damage in TDP-43 and FUS-linked ALS and association of FUS with neuronal DNA damage repair pathways indicate a possible role of deregulated DNA binding function of TDP-43 and FUS in ALS. In this review, we discuss the different ALS disease subtypes, crosstalk of etiopathologies in disease progression, available animal models and their limitations, and recent advances in understanding the specific involvement of RNA/DNA binding proteins, TDP-43 and FUS, in motor neuron diseases.