Single copy/knock-in models of ALS SOD1 in C. elegans suggest loss and gain of function have different contributions to cholinergic and glutamatergic neurodegeneration

Mutations in Cu/Zn superoxide dismutase 1 (SOD1) lead to Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease that disproportionately affects glutamatergic and cholinergic motor neurons. Previous work with SOD1 overexpression models supports a role for SOD1 toxic gain of function in ALS pathogenesis. However, the impact of SOD1 loss of function in ALS cannot be directly examined in overexpression models. In addition, overexpression may obscure the contribution of SOD1 loss of function in the degeneration of different neuronal populations. Here, we report the first single-copy, ALS knock-in models in C. elegans generated by transposon- or CRISPR/Cas9- mediated genome editing of the endogenous sod-1 gene. Introduction of ALS patient amino acid changes A4V, H71Y, L84V, G85R or G93A into the C. elegans sod-1 gene yielded single-copy/knock-in ALS SOD1 models. These differ from previously reported overexpression models in multiple assays. In single-copy/knock-in models, we observed differential impact of sod-1 ALS alleles on glutamatergic and cholinergic neurodegeneration. A4V, H71Y, G85R, and G93A animals showed increased SOD1 protein accumulation and oxidative stress induced degeneration, consistent with a toxic gain of function in cholinergic motor neurons. By contrast, H71Y, L84V, and G85R lead to glutamatergic neuron degeneration due to sod-1 loss of function after oxidative stress. However, dopaminergic and serotonergic neuronal populations were spared in single-copy ALS models, suggesting a neuronal-subtype specificity previously not reported in invertebrate ALS SOD1 models. Combined, these results suggest that knock-in models may reproduce the neurotransmitter-type specificity of ALS and that both SOD1 loss and gain of toxic function differentially contribute to ALS pathogenesis in different neuronal populations.Peer reviewe

The Lantern, 2020-2021

One Thousand and One is Never Enough • House on Hazel Ave. • Crooked Men at Crooked Alley • Home • Honeybee • The Witch\u27s Daughter • Traveling to Reyu • December 31st, 2019 • The Dominator Rolls the Dice Again • Red Flowers • Military Ball • Drowning in Color • Early Bird • Introspection • Hot Water • Reaching Into Space • Floating Marigolds Before COVID-19 • Smokestack 4 • Longing • His Fifth Year on Amstel Road • Wonderful Moments • Clean Glass • Betty, the Debutante • Teakettles Have it Easy • Fuimos, Somos y Seramos Parte de la Historia de la Isla • Kitchen Table • She Couldn\u27t • Cooling Down • Not so Precious Stones • Domestic Wild • Violet Eater • I Will be Sweet • Flavor of Life • Clogged Artery • All Twenty-Six • The Greatest • From Ashes of War to Golden Cities • A Good Thing • Introduction • Devotion • Life of the Gambler • Impressions: Or a Dining Table\u27s Soliloquy • Looking Glass • Montgomery Pie • Under the Hill • Paperback Lesbian • Girl With Pearl Earring • Your Mirror • Jacket • Illusions • Strawberry Girl (Raw Sugar, Shattered Glass) • I Don\u27t Jam With Instagram • The Morning After Saturday • A Brisk Monday Morning • Emergence • Politeness and Pattern Recognition • Douglas Adams\u27 Guide to Florida • A Love Story With Femininity • Roots • Dysmorphia IIIhttps://digitalcommons.ursinus.edu/lantern/1189/thumbnail.jp

Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry

OBJECTIVES: The Digital Ulcers Outcome (DUO) Registry was designed to describe the clinical and antibody characteristics, disease course and outcomes of patients with digital ulcers associated with systemic sclerosis (SSc). METHODS: The DUO Registry is a European, prospective, multicentre, observational, registry of SSc patients with ongoing digital ulcer disease, irrespective of treatment regimen. Data collected included demographics, SSc duration, SSc subset, internal organ manifestations, autoantibodies, previous and ongoing interventions and complications related to digital ulcers. RESULTS: Up to 19 November 2010 a total of 2439 patients had enrolled into the registry. Most were classified as either limited cutaneous SSc (lcSSc; 52.2%) or diffuse cutaneous SSc (dcSSc; 36.9%). Digital ulcers developed earlier in patients with dcSSc compared with lcSSc. Almost all patients (95.7%) tested positive for antinuclear antibodies, 45.2% for anti-scleroderma-70 and 43.6% for anticentromere antibodies (ACA). The first digital ulcer in the anti-scleroderma-70-positive patient cohort occurred approximately 5 years earlier than the ACA-positive patient group. CONCLUSIONS: This study provides data from a large cohort of SSc patients with a history of digital ulcers. The early occurrence and high frequency of digital ulcer complications are especially seen in patients with dcSSc and/or anti-scleroderma-70 antibodies