The PrPC / PDK1 / TACE signaling axis at the cross-road of several aggregate-prone protein-associated neurodegenerative diseases

The project will investigate whether there are common underlying mechanisms that can cause neurodegenerative brain diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinocerebellar ataxia and frontotemporal dementia. These diseases are all featured in that they lead to the deposition of protein aggregates in the "dying" nerve cells in the brain. With the help of isolated nerve cells and neurons in the intact brain - in disease models for the above mentioned brain diseases - we will find out whether the activation of a an enzyme (3-phosphoinositide-dependent kinase-1 (PDK1)) that add phosphate groups to proteins leads to nerve cell death in the various brain diseases. PDK1-activated phosphorylation of another enzyme (TACE alpha-secretase) triggers translocation of this enzyme from the cell surface and into the nerve cells. TACE alpha-secretase will normally cleave other proteins that are present on the cell surface and thus regulate the cell membrane density of these proteins. In this way, TACE alpha-secretase normally protects nerve cells against the formation of protein aggregation. This protective effect may vanish after PDK1 activation because TACE alpha-secretase disappears from the cell surface. At the same time, this can cause other proteins, which are also regulated by the TACE alpha-secretase, accumulate in the cell membrane. Among other things, the normal prion protein (PrPC) is converted into a harmful prion protein (PrPSc). The hypothesis is that PrPSc can lead to harmful protein aggregates in the nerve cells of the different brain diseases mentioned above. By using the techniques and methods, of which the various partners in the project are experts, this hypothesis will be examined. The goal is to find common causes of brain diseases and identify mechanisms that can be targeted for medical treatment.

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Neurodegenerative diseases such as Alzheimer?s (AD), prion, Parkinson?s (PD) diseases, Amyotrophic Lateral Sclerosis (ALS), Spinocerebellar Ataxia type 1 (SCA-1) and Frontotemporal Dementia (FTD) are characterized by distinct etiologies and pathophysiological features. These diseases may share common pathogenic cascades. The identification of common neurodegenerative pathways will contribute to design potent therapies against these disorders. The Principal Investigator provided evidence for deregulation of common signaling pathways in prion diseases and AD. Prion infection or amyloid A-beta peptides leads to activation of the 3-phosphoinositide-dependent kinase-1 (PDK1), which cancels the neuroprotective activity of TACE alpha-secretase at the plasma membrane by TACE internalization. TACE loses its activity towards three main substrates: (i) TNFalpha receptors (TNFR), which accumulate at the plasma membrane leading to TNFalpha-associated inflammation, (ii) the cellular prion protein (PrPC), favoring its conversion into pathogenic prions (PrPSc) in prion diseases, and (iii) the amyloid precursor protein, favoring the accumulation of neurotoxic Abeta in AD. We hypothesize that the interaction of PrPC with such proteins found in PD (alpha-synuclein), ALS (SOD1 mutants), SCA-1 (ataxin-1), FTD (Tau) deviates its signaling function and transduces toxic signals for neurons, but also enables their transcellular spreading in the nervous system. Our goal is to assess whether PrPC-dependent overactivation of the PDK1/TACE/TNFR pathway contributes to neuroinflammation (WP1), accumulation (WP2) and spreading (WP3) of these aggregate-prone proteins and thereby represents a putative therapeutic target to combat aggregate-prone protein-associated neurodegenerative pathologies (WP4).