Alzheimer’s disease

A pathological role of the Hsp40 protein Ydj1/DnaJA1 in models of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common form of dementia with millions of people affected worldwide. Pathophysiological manifestations of AD include the extracellular accumulation of amyloid beta (Abeta) peptides, products of the proteolytic cleavage of the amyloid precursor protein APP. Increasing evidence suggests that Abeta peptides also accumulate intracellularly, triggering neurotoxic events such as mitochondrial dysfunction. However, the molecular factors driving formation and toxicity of intracellular Abeta are poorly understood. In our recent study [EMBO Mol Med 2022 – e13952], we used different eukaryotic model systems to identify such factors. Based on a genetic screen in yeast and subsequent molecular analyses, we found that both the yeast chaperone Ydj1 and its human ortholog DnaJA1 physically interact with Abeta, facilitate the aggregation of Abeta (…)

The role of lipids in autophagy and its implication in neurodegeneration

Neurodegenerative diseases are, at present, major socio-economic burdens without effective treatments and their increasing prevalence means that these diseases will be a challenge for future generations. Neurodegenerative diseases may differ in etiology and pathology but are often caused by the accumulation of dysfunctional and aggregation-prone proteins. Autophagy, a conserved cellular mechanism, deals with cellular stress and waste product build-up and has been shown to reduce the accumulation of dysfunctional proteins in animal models of neurodegenerative diseases. Historically, progress in understanding the precise function of lipids has traditionally been far behind other biological molecules (like proteins) but emerging works demonstrate the importance of lipids in the autophagy pathway and how the disturbance of lipid metabolism is connected to neurodegeneration. Here we review how altered autophagy and the disturbance of lipid metabolism, particularly of phosphoinositols and sphingolipids, feature in neurodegenerative diseases and address work from the field that suggests that these potentially offer an opportunity of therapeutic intervention.

Recent progress in the role of autophagy in neurological diseases

Autophagy (here refers to macroautophagy) is a catabolic pathway by which large protein aggregates and damaged organelles are first sequestered into a double-membraned structure called autophagosome and then delivered to lysosome for destruction. Recently, tremendous progress has been made to elucidate the molecular mechanism and functions of this essential cellular metabolic process. In addition to being either a rubbish clearing system or a cellular surviving program in response to different stresses, autophagy plays important roles in a large number of pathophysiological conditions, such as cancer, diabetes, and especially neurodegenerative disorders. Here we review recent progress in the role of autophagy in neurological diseases and discuss how dysregulation of autophagy initiation, autophagosome formation, maturation, and/or autophagosome-lysosomal fusion step contributes to the pathogenesis of these disorders in the nervous system.

Making the final cut: pathogenic amyloid-β peptide generation by γ-secretase

Alzheimer´s disease (AD) is a devastating neurodegenerative disease of the elderly population. Genetic evidence strongly suggests that aberrant generation and/or clearance of the neurotoxic amyloid-β peptide (Aβ) is triggering the disease. Aβ is generated from the amyloid precursor protein (APP) by the sequential cleavages of β- and γ-secretase. The latter cleavage by γ-secretase, a unique and fascinating four-component protease complex, occurs in the APP transmembrane domain thereby releasing Aβ species of 37-43 amino acids in length including the longer, highly pathogenic peptides Aβ42 and Aβ43. The lack of a precise understanding of Aβ generation as well as of the functions of other γ-secretase substrates has been one factor underlying the disappointing failure of γ-secretase inhibitors in clinical trials, but on the other side also been a major driving force for structural and in depth mechanistic studies on this key AD drug target in the past few years. Here we (…)