Parkinson's disease (PD), an adult neurodegenerative disorder, has been clinically linked to the lysosomal storage disorder Gaucher disease (GD), but the mechanistic connection is not known. Here, we ...show that functional loss of GD-linked glucocerebrosidase (GCase) in primary cultures or human iPS neurons compromises lysosomal protein degradation, causes accumulation of α-synuclein (α-syn), and results in neurotoxicity through aggregation-dependent mechanisms. Glucosylceramide (GlcCer), the GCase substrate, directly influenced amyloid formation of purified α-syn by stabilizing soluble oligomeric intermediates. We further demonstrate that α-syn inhibits the lysosomal activity of normal GCase in neurons and idiopathic PD brain, suggesting that GCase depletion contributes to the pathogenesis of sporadic synucleinopathies. These findings suggest that the bidirectional effect of α-syn and GCase forms a positive feedback loop that may lead to a self-propagating disease. Therefore, improved targeting of GCase to lysosomes may represent a specific therapeutic approach for PD and other synucleinopathies.
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► Mechanistic link between Gaucher disease and synucleinopathies such as Parkinson's ► Lysosomal glucosylceramide accumulation in Gaucher stabilizes α-synuclein oligomers ► α-synuclein inhibits lysosomal trafficking of glucocerebrosidase in synucleinopathies ► Glucocerebrosidase may be a therapeutic target in synucleinopathies
Neurodegenerative diseases represent an increasing burden in our aging society, yet the underlying metabolic factors influencing onset and progression remain poorly defined. The relationship between ...impaired IGF-1/insulin-like signaling (IIS) and lifespan extension represents an opportunity to investigate the interface of metabolism with age-associated neurodegeneration. Using data sets of established DAF-2/IIS-signaling components in Caenorhabditis elegans, we conducted systematic RNAi screens in worms to select for daf-2-associated genetic modifiers of α-synuclein misfolding and dopaminergic neurodegeneration, two clinical hallmarks of Parkinson’s disease. An outcome of this strategy was the identification of GPI-1/GPI, an enzyme in glucose metabolism, as a daf-2-regulated modifier that acts independent of the downstream cytoprotective transcription factor DAF-16/FOXO to modulate neuroprotection. Subsequent mechanistic analyses using Drosophila and mouse primary neuron cultures further validated the conserved nature of GPI neuroprotection from α-synuclein proteotoxicity. Collectively, these results support glucose metabolism as a conserved functional node at the intersection of proteostasis and neurodegeneration.
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•Insulin signaling modulates neurodegeneration in fly and worm Parkinson’s models•Reduced insulin-signaling screen reveals metabolic modifiers of protein misfolding•A glycolytic enzyme, GPI, is neuroprotective across worms, flies, and mouse neurons•GPI functions independently of DAF-16/FOXO to modulate proteostasis via glycolysis
Knight et al. screened for modifiers of α-synuclein misfolding and dopaminergic neurodegeneration, two clinical hallmarks of Parkinson’s disease, in worms with decreased IIS signaling. They identify the glycolytic enzyme GPI, which plays a conserved DAF-16/FOXO-independent role in worms, flies, and primary mouse neurons, integrating metabolic regulation with proteotoxicity and dopaminergic neurodegeneration.
The polycomb repressive complex 2 (PRC2) methylates lysine 27 of histone H3 (H3K27) through its catalytic subunit Ezh2. PRC2-mediated di- and tri-methylation (H3K27me2/H3K27me3) have been ...interchangeably associated with gene repression. However, it remains unclear whether these two degrees of H3K27 methylation have different functions. In this study, we have generated isogenic mouse embryonic stem cells (ESCs) with a modified H3K27me2/H3K27me3 ratio. Our findings document dynamic developmental control in the genomic distribution of H3K27me2 and H3K27me3 at regulatory regions in ESCs. They also reveal that modifying the ratio of H3K27me2 and H3K27me3 is sufficient for the acquisition and repression of defined cell lineage transcriptional programs and phenotypes and influences induction of the ESC ground state.
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•H3K27me2/H3K27me3 are redistributed during ESC differentiation•H3K27 methylation recapitulates changes during differentiation in Ezh2-edited ESCs•In pluripotent culture conditions, Ezh2-edited ESCs activate the neurogenic program•Ezh2-edited ESCs are refractory to a 2i-medium-induced “ground state”
Juan et al. use genome editing to subtly modify H3K27 methylation states (H3K27me2/H3K27me3) and report that such perturbation influences the ability of ESCs to differentiate into preferential cell lineages and acquire a “ground state.”
Angular distributions of OH inelastically scattered from the surfaces of the reactive hydrocarbon liquids squalane (fully saturated) and squalene (partially unsaturated) have been measured. A pulsed, ...rotationally cold molecular beam (E i = 35 kJ mol–1) of OH was scattered from refreshed liquid surfaces in a vacuum. Spatially and temporally resolved OH number densities were measured by pulsed, planar laser-induced fluorescence. Results are compared with those for the inert liquid perfluoropolyether. The clearly asymmetric distributions for 45° incidence add to the weight of evidence for predominantly impulsive scattering from all three liquids. However, we propose that significant differences in their shapes may be diagnostic of contrasting reaction mechanisms. Direct, near-specular trajectories survive preferentially on squalene, consistent with an addition mechanism removing those at more backward angles. This trend is reversed for squalane, as expected for direct abstraction. The results reinforce the need to consider the effects of composition-dependent contributions from different reaction mechanisms in the modeling of OH-aging of atmospheric aerosol particles.
Genomic multiplication of the locus-encoding human α-synuclein (α-syn), a polypeptide with a propensity toward intracellular misfolding, results in Parkinson's disease (PD). Here we report the ...results from systematic screening of nearly 900 candidate genetic targets, prioritized by bioinformatic associations to existing PD genes and pathways, via RNAi knockdown. Depletion of 20 gene products reproducibly enhanced misfolding of α-syn over the course of aging in the nematode Caenorhabditis elegans. Subsequent functional analysis of seven positive targets revealed five previously unreported gene products that significantly protect against age- and dose-dependent α-syn-induced degeneration in the dopamine neurons of transgenic worms. These include two trafficking proteins, a conserved cellular scaffold-type protein that modulates G protein signaling, a protein of unknown function, and one gene reported to cause neurodegeneration in knockout mice. These data represent putative genetic susceptibility loci and potential therapeutic targets for PD, a movement disorder affecting ≈2% of the population over 65 years of age.
To evaluate the literature regarding unilateral landing biomechanics and dynamic postural stability in individuals with and without chronic ankle instability (CAI).
Four online databases (PubMed, ...ScienceDirect, Scopus, and SportDiscus) were searched from the earliest records to 31 January 2018, as well as reference sections of related journal articles, to complete the systematic search. Studies investigating the influence of CAI on unilateral landing biomechanics and dynamic postural stability were systematically reviewed and evaluated.
Twenty articles met the criteria and were included in the systematic review. Individuals with CAI were found to have deficits in dynamic postural stability on the affected limb with medium to large effect sizes and altered lower extremity kinematics, most notably in the ankle and knee, with medium to large effect sizes. Additionally, greater loading rates and peak ground reaction forces, in addition to reductions in ankle muscle activity were also found in individuals with CAI during unilateral jump-landing tasks.
Individuals with CAI demonstrate dynamic postural stability deficits, lower extremity kinematic alterations, and reduced neuromuscular control during unilateral jump-landings. These are likely factors that contribute recurrent lateral ankle sprain injuries during dynamic activity in individuals with CAI.
•Individuals with CAI demonstrate dynamic postural stability deficts.•Altered kinematic patterns and neuromuscular control are associated with CAI.•Clinicians should aim to restore altered movement patterns during rehabilitation.•More studies are needed to understand the link between kinetics and injury.
Muscle activity from the slipping leg have been previously used to analyze slip induced falls. However, the impact of casual alternative footwear on slipping leg muscle activity when exposed to ...slippery environments is still unknown. The purpose of the study was to analyze the impact of alternative footwear (crocs (CC) and flip-flops (FF)) compared to slip-resistant footwear (LT) on lower extremity muscle activity when exposed to dry gait (NG), unexpected (US), alert (AS), and expected slips (ES). Eighteen healthy males (age: 22.3 ± 2.2 years; height: 177.7 ± 6.9 cm; weight: 79.3 ± 7.6 kg) completed the study in a repeated measures design in three footwear sessions separated by 48 h. Electromyography (EMG) muscle activity from four muscles of the lead/slipping leg was measured during the stance phase of the gait-slip trials. A 3 (footwear) × 4 (gait-slip trials) repeated measures analysis of variance was used to analyze EMG dependent variables mean, peak, and percent of maximal voluntary contraction. Greater lower extremity muscle activation during the stance phase was seen in US and AS conditions compared to NG and ES. In addition, footwear differences were seen for the alternative footwear (CC and FF) during US and AS, while the low top slip resistant shoe had no differences across all gait trials, suggesting it as the most efficient footwear of choice, especially when maneuvering slippery flooring conditions, either with or without the knowledge of an impending slip.
The Star Excursion Balance Test (SEBT) is a common assessment used across clinical and research settings to test dynamic standing balance. The primary measure of this test is maximal reaching ...distance performed by the non-stance limb. Response time (RT) is a critical cognitive component of dynamic balance control and the faster the RT, the better the postural control and recovery from a postural perturbation. However, the measure of RT has not been done in conjunction with SEBT, especially with musculoskeletal fatigue. The purpose of this study is to examine RT during a SEBT, creating a modified SEBT (mSEBT), with a secondary goal to examine the effects of muscular fatigue on RT during SEBT. Sixteen healthy young male and female adults age: 20 ± 1 years; height: 169.48 ± 8.2 cm; weight: 67.93 ± 12.7 kg performed the mSEBT in five directions for three trials, after which the same was repeated with a response time task using Blazepod™ with a random stimulus. Participants then performed a low-intensity musculoskeletal fatigue task and completed the above measures again. A 2 × 2 × 3 repeated measures ANOVA was performed to test for differences in mean response time across trials, fatigue states, and leg reach as within-subjects factors. All statistical analyses were conducted in JASP at an alpha level of 0.05. RT was significantly faster over the course of testing regardless of reach leg or fatigue state (
= 0.023). Trial 3 demonstrated significantly lower RT compared to Trial 1 (
= 0.021). No significant differences were found between fatigue states or leg reach. These results indicate that response times during the mSEBT with RT is a learned skill that can improve over time. Future research should include an extended familiarization period to remove learning effects and a greater fatigue state to test for differences in RT during the mSEBT.
Balance performance have been shown to be influenced by footwear design characteristics and physiological workloads. This study was conducted to assess the impact of two military footwear, standard ...(STD) and minimalist (MIN) boots, on human balance before (PRE) and after (POST) a simulated military type, load carriage exercise. Twenty two male participants age: 22.14 ± 2.68 years; height: 176.69 ± 6.82 cm; weight: 79.81 ± 9.70 kg were tested for balance in bilateral and unilateral stances with and without challenging sensory information and using a star excursion balance test (SEBT). Center of pressure postural sway variables from different balance testing conditions and reach distances from SEBT, were analyzed using a 2(STD-MIN) x 2(PRE-POST) repeated measures analysis of variance. Results revealed significantly greater postural sway in the STD boot and in POST workload conditions. Decrements in balance can be attributed to boot design characteristics and muscular exertion due to the workload.
•On average, superior static-balance was exhibited when wearing the minimalist boot.•Significantly worse static-balance was demonstrated after the physiological workload.•Specific footwear characteristics should be implemented for increased performance.
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