Gait quality scoring data of Franches-Montagnes stallions at walk and trot on a treadmill by experts of the breed and their reliability

This article presents the data obtained from the scoring of 24 stallions of the Franches-Montagnes (FM) horse breed by six experts of this breed. The experts scored six traits at walk and eight at trot from the video recordings of these stallions walking and trotting on a treadmill during an incremental speed test. The scores were given on a scale of one to nine. All experts scored the same videos twice (two scoring tests) with a time interval of two years, and without feedback from the first scoring. Video sequences were presented in a different order between first and second scoring. The inter- and intra-rater reliability of the data was assessed using intraclass correlation coefficients (ICC) to evaluate its quality

Determining Objective Parameters to Assess Gait Quality in Franches-Montagnes Horses for Ground Coverage and Over-Tracking - Part 1: At Walk

Ground coverage and over-tracking are two gait quality traits describing the forward movement of the front respectively the hind limbs in relation to stride length and over-tracking distance. To investigate the complex interplay of different movement patterns in ground coverage and over-tracking, limb and body kinematics of 24 Franches-Montagnes (FM) stallions were measured with 3D optical motion capture (OMC) on a treadmill during an incremental speed test at the walk (1.4-2.0 m/s). The significance and amount of explained variance of kinematic parameters on stride length and over-tracking distance were estimated using linear mixed-effect models, with speed and horse as random effects. Two separate models were tested: a full model with all parameters measurable by OMC, and a reduced model with a subset of parameters also measurable with inertial measurement units (IMUs). The kinematic parameters were correlated to the subjective scores from six breeding experts to interpret their external validity. The parameter for ground coverage at the walk, explaining most of the variance in stride length, were the maximal forelimb retraction angle (11%) measured with OMC, and the range of pelvis pitch (10%) if measuring with IMUs. The latter was also the most relevant for quantifying over-tracking, explaining 24% to 33% of the variance in the over-tracking distance. The scores from most breeding experts were significantly correlated (r ≥ |0.41|) with the fore- and hind limb protraction angles, which reflect the textual definition of ground coverage and over-tracking. Both gait quality traits can be objectively quantified using either OMC or IMUs

Determining Objective Parameters to Assess Gait Quality in Franches-Montagnes Horses for Ground Coverage and Over-Tracking - Part 2: At Trot

In gait quality assessments of horses, stride length (SL) is visually associated with spectacular movements of the front limbs, and described as ground coverage, while the movement of the hind limb under the body is supposedly essential to a longer over-tracking distance (OTD). To identify movement patterns with strong associations to SL and OTD, limb and body kinematics of 24 Franches-Montagnes (FM) stallions were measured with 3D optical motion capture (OMC) on a treadmill during an incremental speed test at trot (3.3–6.5 m/s). These measurements were correlated to the scores of ground coverage and over-tracking from six breeding experts. The amount of explained variance of parameters on SL and OTD were estimated using linear mixed-effect models in two models: a full model with all parameters measurable with OMC, and a reduced model with a subset of parameters measurable with inertial measurement units (IMUs). The front limb stance duration (16%) and OTD (7%) measured with OMC, or the OMC parameters front limb stance duration (24%) and suspension duration (14%) measurable with IMUs explained most variance in SL. However, four of six breeding experts were also significantly correlated (r>|0.41|) to front limb protraction angle. OTD variance was explained with OMC parameters suspension duration (10%) and hind limb contralateral pro-retraction angles (9%) or IMU-measurable parameters suspension duration (20%) and maximal pelvis pitch (5%). Four experts’ scores for over-tracking were correlated to suspension duration. These results underscore the need for precise definitions of gait quality traits

Different neuroinflammatory profile in amyotrophic lateral sclerosis and frontotemporal dementia is linked to the clinical phase

Objective To investigate the role of neuroinflammation in asymptomatic and symptomatic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mutation carriers. Methods The neuroinflammatory markers chitotriosidase 1 (CHIT1), YKL-40 and glial fibrillary acidic protein (GFAP) were measured in cerebrospinal fluid (CSF) and blood samples from asymptomatic and symptomatic ALS/FTD mutation carriers, sporadic cases and controls by ELISA. Results CSF levels of CHIT1, YKL-40 and GFAP were unaffected in asymptomatic mutation carriers (n=16). CHIT1 and YKL-40 were increased in gALS (p<0.001, n=65) whereas GFAP was not affected. Patients with ALS carrying a CHIT1 polymorphism had lower CHIT1 concentrations in CSF (-80%) whereas this polymorphism had no influence on disease severity. In gFTD (n=23), increased YKL-40 and GFAP were observed (p<0.05), whereas CHIT1 was nearly not affected. The same profile as in gALS and gFTD was observed in sALS (n=64/70) and sFTD (n=20/26). CSF and blood concentrations correlated moderately (CHIT1, r=0.51) to weak (YKL-40, r=0.30, GFAP, r=0.39). Blood concentrations of these three markers were not significantly altered in any of the groups except CHIT1 in gALS of the Ulm cohort (p<0.05). Conclusion Our data indicate that neuroinflammation is linked to the symptomatic phase of ALS/FTD and shows a similar pattern in sporadic and genetic cases. ALS and FTD are characterised by a different neuroinflammatory profile, which might be one driver of the diverse presentations of the ALS/FTD syndrome

Different CSF protein profiles in amyotrophic lateral sclerosis and frontotemporal dementia with C9orf72 hexanucleotide repeat expansion

Objectives: The hexanucleotide repeat expansion in the C9orf72 gene is the most common mutation associated with amyotrophic lateral sclerosis (C9-ALS) and frontotemporal dementia (C9-FTD). Until now, it is unknown which factors define whether C9orf72 mutation carriers develop ALS or FTD. Our aim was to identify protein biomarker candidates in the cerebrospinal fluid (CSF) which differentiate between C9-ALS and C9-FTD and might be indicative for the outcome of the mutation. Methods We compared the CSF proteome of 16 C9-ALS and 8 C9-FTD patients and 11 asymptomatic C9orf72 mutation carriers (CAR) by isobaric tags for relative and absolute quantitation. Eleven biomarker candidates were selected from the pool of differentially regulated proteins for further validation by multiple reaction monitoring and single-molecule array in a larger cohort (n=156). Results In total, 2095 CSF proteins were identified and 236 proteins were significantly different in C9-ALS versus C9-FTD including neurofilament medium polypeptide (NEFM) and chitotriosidase-1 (CHIT1). Eight candidates were successfully validated including significantly increased ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) levels in C9-ALS compared with C9-FTD and controls and decreased neuronal pentraxin receptor (NPTXR) levels in C9-FTD versus CAR. Conclusions: This study presents a deep proteomic CSF analysis of C9-ALS versus C9-FTD patients. As a proof of concept, we observed higher NEFM and CHIT1 CSF levels in C9-ALS. In addition, we also show clear upregulation of UCHL1 in C9-ALS and downregulation of NPTXR in C9-FTD. Significant differences in UCHL1 CSF levels may explain diverging ubiquitination and autophagy processes and NPTXR levels might reflect different synapses organisation processes

Sumoylation inhibits α-synuclein aggregation and toxicity

Sumoylation of α-synuclein decreases its rate of aggregation and its deleterious effects in vitro and in vivo

Extracellular vesicle sorting of α-Synuclein is regulated by sumoylation

Extracellular α-Synuclein has been implicated in interneuronal propagation of disease pathology in Parkinson’s Disease. How α-Synuclein is released into the extracellular space is still unclear. Here, we show that α-Synuclein is present in extracellular vesicles in the central nervous system. We find that sorting of α-Synuclein in extracellular vesicles is regulated by sumoylation and that sumoylation acts as a sorting factor for targeting of both, cytosolic and transmembrane proteins, to extracellular vesicles. We provide evidence that the SUMO-dependent sorting utilizes the endosomal sorting complex required for transport (ESCRT) by interaction with phosphoinositols. Ubiquitination of cargo proteins is so far the only known determinant for ESCRT-dependent sorting into the extracellular vesicle pathway. Our study reveals a function of SUMO protein modification as a Ubiquitin-independent ESCRT sorting signal, regulating the extracellular vesicle release of α-Synuclein. We deciphered in detail the molecular mechanism which directs α-Synuclein into extracellular vesicles which is of highest relevance for the understanding of Parkinson’s disease pathogenesis and progression at the molecular level. We furthermore propose that sumo-dependent sorting constitutes a mechanism with more general implications for cell biology.Instituto de Investigaciones Bioquímicas de La Plat

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology