TAOK1 is associated with neurodevelopmental disorder and essential for neuronal maturation and cortical development.

Thousand and one amino-acid kinase 1 (TAOK1) is a MAP3K protein kinase, regulating different mitogen-activated protein kinase pathways, thereby modulating a multitude of processes in the cell. Given the recent finding of TAOK1 involvement in neurodevelopmental disorders (NDDs), we investigated the role of TAOK1 in neuronal function and collected a cohort of 23 individuals with mostly de novo variants in TAOK1 to further define the associated NDD. Here, we provide evidence for an important role for TAOK1 in neuronal function, showing that altered TAOK1 expression levels in the embryonic mouse brain affect neural migration in vivo, as well as neuronal maturation in vitro. The molecular spectrum of the identified TAOK1 variants comprises largely truncating and nonsense variants, but also missense variants, for which we provide evidence that they can have a loss of function or dominant-negative effect on TAOK1, expanding the potential underlying causative mechanisms resulting in NDD. Taken together, our data indicate that TAOK1 activity needs to be properly controlled for normal neuronal function and that TAOK1 dysregulation leads to a neurodevelopmental disorder mainly comprising similar facial features, developmental delay/intellectual disability and/or variable learning or behavioral problems, muscular hypotonia, infant feeding difficulties, and growth problems.

Impact of a fatigue management in work programme on meeting work demands of individuals with rheumatic diseases: A pilot study.

INTRODUCTION: Work disability and job loss are serious consequences of rheumatic diseases (RDs), and fatigue is a symptom of RDs commonly reported to have an impact on work performance. A FAtigue ManagEment in Work (FAME-W) programme was developed to facilitate the self-management of fatigue in work. The present pilot study explored if FAME-W could facilitate individuals with RDs to manage fatigue in work and improve their ability to meet work demands. METHODS: Twenty-seven individuals with a variety of rheumatic diagnoses completed a 4-week, 2-h occupational therapy-led self-management programme. Each week focused on fatigue-related topics, including fatigue and activity management, pain management and joint protection, mental well-being, effective communication with employers and work colleagues, and employment legislation. Individual workplace ergonomic assessments were also offered. Study measures (work function, fatigue, pain, mood and self-efficacy) were completed prior to starting FAME-W, immediately post-intervention and 12 weeks post-intervention. RESULTS: Participants (56% male) had a mean age of 43 years. No significant improvements were observed immediately post-programme. However, at the 12-week follow-up, significant improvements were reported in meeting work demands (scheduling [p = 0.046], output [p = 0.002], physical [p = 0.003], mental [p = 0.016]), fatigue [p = 0.001], pain [p = 0.01], anxiety [p = 0.001], depression [p < 0.001], self-efficacy [p < 0.001] and Arthritis Impact Measurement Scales 2-Short Form (physical: p = 0.005; symptoms: p = 0.010; affect: p = 0.010; social: p = 0.001). CONCLUSIONS: Significant improvements were reported in participants' ability to meet various demands of their work 3 months post-FAME-W. These findings suggest that FAME-W has the potential to assist individuals with RDs to meet the demands of their work, although further research is required to test the effectiveness of this intervention.

Life-course determinants of cognitive reserve (CR) in cognitive aging and dementia - a systematic literature review.

OBJECTIVES: The concept of cognitive reserve (CR) is defined as a moderator, which allows an individual to preserve cognition despite underlying brain pathology. There is no consensus of what potentially modifiable CR determinants are of greatest importance. The aim of this review was to identify life-course factors which protect older individuals from expressing cognitive decline despite the presence of brain pathology. METHOD: A systematic review search was performed in MEDLINE (1946-06/09/13), EMBASE (1947-06/09/13), and PsycheInfo (1967-06/09/13). We included studies examining CR in the context of the four commonest subtypes of dementia, mild cognitive impairment or healthy aging. Studies which combined measurement of underlying dementia-related neuropathology, cognitive function, and factors providing CR in a single model were accepted. We performed a qualitative synthesis of the results. RESULTS: Thirty-four studies out of 9229 screened records met our inclusion criteria and were therefore quality assessed and data extracted. Variation in CR definition made comparison across studies difficult. One hundred and forty-four out of 156 models examined education and occupation: overall, 58% of eligible models classified education and 60% occupation as a CR determinant, with 12% and 44% of those, respectively, being of high quality. Within healthy population suitable to inform preventative interventions, there was consistent evidence for education having a protective effect on general cognition in the face of multiple brain burden measures, while occupation presented inconclusive results within cognitive groups. CONCLUSIONS: Further research on modifiable determinants of CR beyond education/occupation including early-life factors and consensus on CR definition are warranted.

A role for p53 in the beta-amyloid-mediated regulation of the lysosomal system.

Beta-amyloid accumulates around neurons in Alzheimer's disease and is thought to contribute to the neurodegenerative process. This study examined the role of the tumour suppressor protein, p53, in the neurodegenerative pathway, with focus on the interaction of p53 with the lysosomal system. beta-Amyloid increased expression of p53 and its transcription target, Bax, in cultured cortical neurons. In addition, A beta increased the association of phospho-p53(ser15) with the lysosomal compartment and this correlated with destabilization of the lysosomal membrane and a concomitant increase in cytosolic cathepsin-L activity. These effects of beta-amyloid were abolished by the p53 inhibitor, pifithrin-alpha, and siRNA-mediated knockdown of p53, demonstrating that p53 is a critical regulator of lysosomal integrity and the induction of cathepsin-L protease activity. In addition, activation of the apoptotic cascade was abolished by pifithrin-alpha. We conclude that p53 associates with the lysosome to regulate a lysosomal branch of the apoptotic cascade which contributes to beta-amyloid-mediated neurodegeneration.