Fred Van Leuven, Catholic University, Leuven, Belgium
Todd E. Golde, University of Florida, USA
Larry C. Walker, Emory University, Atlanta, USA
Hilal Lashuel, EPFL, Lausanne, Switzerland
David Morgan, University of South Florida, Tampa, USA
Donato Di Monte, DZNE, Bonn, Germany
Aggregation of misfolded proteins in insoluble fibrous structures called amyloid represents a common feature of several neurodegenerative disorders, including Alzheimer´s disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxias. Protein aggregates may occur either within the cell or in extracellular space and have been used to classify and diagnose these diseases: characterization of a spectrum of disorders where protein aggregation is a major component may be particularly helpful in new approaches towards rational therapeutics.
While most of these deposits were discovered by neuropathologists several decades ago, their molecular composition and biochemical properties have only recently been unraveled and are still a matter of intense investigation. Based on postmortem analysis, it has been argued that amyloids may only represent the „tomb stone" of a degenerating cell body, and do not account for an underlying degenerative process. Likewise, extracellular deposits of β-amyloid peptides (Aβ) have been thought to be protective since they could function as detoxifing sites of potentially neurotoxic fibrils and oligomers. However, data showing that deposition of Aβ may actually precede the onset of clinical dementia by decades and therefore represent the earliest detectable feature of AD stand in contrast to this view. Familar forms of aggregation disorders have helped understand the pathogenetic mechanism, however, it is unresolved whether sporadic forms follow the same molecular pathways.
A common feature of protein misfolding in the above-mentioned neurodegenerative diseases is the presence of cross-β-sheet structures, first discovered by X-ray diffraction analysis. Aβ-sheet structure may represent a common feature of neurodegenerative disease-related amyloid, as this trait is shared by Aβ , α-synuclein and polyglutamine aggregates. Despite this commonality, the mechanisms leading to such a distinct change of the secondary protein conformation can vary and may change even during the course of the same disease.
Factors that may modulate amyloid formation are increase of protein levels (e.g., by genetic dosage alterations, familial PD, Down syndrome, compromised proteasomal clearance), or post-translational protein modifications, including phosphorylation and nitration. These mechanisms have been evaluated as possible treatment targets. Some of these strategies, such as vaccination against Aβ protein aggregates or inhibition of tau phosphorylation by glycogen synthase kinase-3β have recently failed to improve patients´ outcome. While the causes of the failure in clinical trials may be multifactorial, and the initiation of treatments may be too late to exert any measurable degree of improvement, new concepts, sequence and timing of interventions which target aggregates need to be reconsidered before further attempts are made.
Future challenges to protein aggregation disorder research will be discussed in the course:
- Why do neurons with inclusion not exactly match degenerating neurons?
- How does aggregation spread within the brain and does this phenomenon help to explain the involvement/vulnerability of different brain areas?
- Is there functional amyloid that converts into a pathological trait?
- What is the difference between sequence and non-sequence specific amyloids?
- Which role do defolding mechanisms play in neurodegenerative disease?
These are among the topics that will be focus of critical discussion throughout the Course and to reach a more comprehensive understanding of these complex issues, the lectures and debates will encompass detailed molecular, structural and functional analysis. Participation will offer the unique opportunity to interact on a personal basis with the renowned Faculties who, in a collegial atmosphere, will present their latest insights and views on protein aggregation disorders and will stimulate the discussion on unresolved questions and novel research in emerging concepts and ideas.