As life expectancy steadily increases, our aging population is faced with a number of serious public health challenges, including the increased prevalence of neurodegenerative diseases. Like other organs, the nervous system is affected by a loss of cells and cellular functions with increasing age that frequently leads to pathological conditions such as Alzheimer's, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis and spinocerebellar ataxia. Other neurological diseases such as multiple sclerosis, which may occur at younger ages, compound the problem. In Germany, these diseases already affect more than a million people, and the number is expected to increase to 3 million over the next few decades. As completely curing these disorders currently appears out of reach, the challenge for now is to postpone their onset. Accordingly, intense research is focused on understanding the pathogenic mechanisms underlying these conditions and the development of therapeutic options based on this information.
The 32nd Blankenese Conference on ‘Neurodegeneration: From Multiple Sclerosis to Alzheimer's Disease’ (http://web.zmnh.uni-hamburg.de/blankenese_conferences/) brought together leading scientific researchers who apply biomolecular, biophysical, genetic, immunological and cellular strategies to dissect the pathogenic mechanisms of neurodegenerative diseases. The identification of disease-causing genes and genetic risk factors, as well as the molecular pathways by which mutations or polymorphisms lead to neural death, were a further focus of the conference. The final focus was on novel strategies in clinical diagnosis, therapy and prevention. The chairmen of the Blankenese Conferences selected four highlights of the program, which are featured as papers in this minireview series.
In the first paper, Altmeppen et al. investigate the role of the cellular prion protein (PrPC) in neurodegenerative diseases. They describe the two major proteolytic cleavage events under physiological conditions, α-cleavage and shedding, and discuss how the resulting polypeptide fragments affect prion diseases and other proteinopathies. They also analyse the therapeutic potential of a recently identified metalloproteinase that acts as a sheddase of PrPC.
The second review, by Bentmann et al., describes stress granules, foci that form rapidly in the cytoplasm of stressed cells. These granules contain marker proteins, including T-cell internal antigen-1, that co-label pathological cytoplasmic inclusions found in patients with amyotrophic lateral sclerosis or frontotemporal lobar degeneration. The authors propose that stress granules may develop further to pathological inclusions that induce toxic functional changes contributing to neurodegeneration.
In the third paper, Hochgräfe et al., focus on the amyloidogenic protein Tau, which accumulates in the nervous system of patients suffering from Alzheimer's disease and frontotemporal dementias. They describe experiments in mouse models that allowed them to conclude that tauopathies are principally reversible when amyloidogenic Tau is removed. Such models are valuable for validating therapeutic options with regard to cognition and synaptic function.
The last minireview of the series, by Lee et al., summarizes recent advances in studying Huntington's disease using novel mouse models with targeted expression of mutant Huntingtin in specific brain cell types. Their reductionist approach enables dissection of molecular and cellular pathways affected by the disease and the identification of novel targets for therapy.