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CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis

2 weeks 4 days ago
Aggregation of the protein tau defines tauopathies, the most common age-related neurodegenerative diseases, which include Alzheimer's disease and frontotemporal dementia. Specific neuronal subtypes are selectively vulnerable to tau aggregation, dysfunction, and death. However, molecular mechanisms underlying cell-type-selective vulnerability are unknown. To systematically uncover the cellular factors controlling the accumulation of tau aggregates in human neurons, we conducted a genome-wide...
Avi J Samelson

Anti-TLR2 immunotherapy modulates neuron-to-oligodendrocyte propagation of α-synuclein in mouse and human models

2 weeks 4 days ago
Intracellular accumulation of α-synuclein (αSyn) aggregates is a hallmark of synucleinopathies, such as Parkinson's disease (PD) and multiple system atrophy (MSA). In MSA, αSyn aggregates form glial cytoplasmic inclusions (GCIs) in oligodendrocytes, despite their low expression of αSyn. Here, we demonstrate that neuron-to-oligodendrocyte propagation of αSyn, via Toll-like receptor 2 (TLR2) contributes to GCI formation. Male transgenic mice expressing the A53T mutant human αSyn exclusively in...
Eun-Jin Bae

Spinal cord stimulation therapy for gait impairment in Parkinson's disease: a double-blinded, randomised feasibility trial with an open extension

2 weeks 4 days ago
A trial of spinal cord stimulation (SCS) was performed in people with gait-impaired Parkinson's (ClinicalTrials.gov: NCT05110053). Fourteen patients underwent gait assessments and [^(18)F]-FDG and [^(18)F]-FEOBV PET at baseline, six, and twelve months after SCS. Twelve participants were randomised to six-month MicroBurst or sham, followed by six-month extension with stimulation. The primary outcomes were feasibility and safety, as captured by the trial process measures and nature and frequency...
Miriam Højholt Terkelsen

Cytokine-induced senescence in tumors is based on sustained activation of STAT1- and NFkappaB-dependent gene regulatory signatures

2 weeks 4 days ago
Senescence is a tripartite cellular phenotype characterized by permanent growth arrest, resistance to apoptosis, and high secretory activity. Besides its physiological role in embryonic development and pathophysiological contribution to age-related tissue degeneration, in the context of tumor development senescence is an important suppressor mechanism, that counteracts accelerated proliferation. Among the many stressors that induce senescence is the external stimulation by cytokines. Although...
Maximilian Rentschler

Exploring the nexus between inflammation and mobility through the lens of healthy aging: current scenario and future perspectives

2 weeks 4 days ago
Aging is characterized by a progressive decline in physiological resilience and functional capacity, often accompanied by chronic, low-grade systemic inflammation, a phenomenon termed "inflammaging". This persistent inflammatory milieu contributes significantly to musculoskeletal degeneration, impaired neuromotor coordination, and reduced mobility, collectively diminishing quality of life, particularly among older adults. Key biological drivers of inflammaging include cellular senescence, immune...
Rachael Patusco

Heritability of intrinsic human life span is about 50% when confounding factors are addressed

2 weeks 4 days ago
How heritable is human life span? If genetic heritability is high, longevity genes can reveal aging mechanisms and inform medicine and public health. However, current estimates of heritability are low-twin studies show heritability of only 20 to 25%, and recent large pedigree studies suggest it is as low as 6%. Here we show that these estimates are confounded by extrinsic mortality-deaths caused by extrinsic factors such as accidents or infections. We use mathematical modeling and analyses of...
Ben Shenhar