What is the Link Between Protein Aggregation and Interneuronal Lesion Propagation in Neurodegenerative Disease?

Abstract

During the past 10-15 years it has become clear that most major neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, ALS, tauopathies, prion diseases and trinucleotide repeat diseases – henceforth to be referred to collectively as AANDs) share cellular and systemic features that suggest a common underlying mechanism of pathogenesis. At the cellular level, our understanding of the common aspects of AAND pathogenesis can be most simply summarized in terms of the downstream consequences of uncontrollable protein oligomerization and aggregation in postmitotic cells. The aggregated proteins block or disrupt normal proteosomal turnover and autophagy and become abnormally modified over time, generating toxicity via multiple pathways (mitochondrial damage, increased intracellular Ca++, caspase activation etc.) eventually leading to neurodegeneration and neuron death. This hypothesis is consistent with a key genetic similarity between these diseases – e.g. that familial forms are typically caused by autosomal dominant mutations that favor aggregation (in the case of asyn, tau, PrP and SOD1) or formation (in the case of APP and CAG repeat sequences) of disease-specific, aggregationprone proteins. These similarities have suggested to many that a single central defect (i.e. the failure of normal protein folding) lies at the heart of most or all of the diseases listed above, and has led to them being categorized be some as “protein misfolding diseases”. While the importance of aggregate formation (and its attendant cellular dysfunctions) in each of these diseases is well established and has been intensively studied, our understanding of the intercellular and systemic aspects of these diseases is less detailed. That said, enough has been learned about their roles in neuronal biology and pathobiology and in the neuropathogenesis of AANDs to generate a general consensus that AAND development is 1) not cell autonomous and 2) that AANDs have another common hallmark– the progressive involvement of synaptically connected regions of the CNS over time in disease-specific patterns. Furthermore, it has become clear that important synergistic interactions between specific aggregation-prone proteins (tau and asyn (83), PrP and APP/Abeta (134), PrP and tau (216), PrP and asyn (95) may occur at both at the cellular and interneuronal level that affect the pathogenesis of specific AANDs. However, while neurofibrillary lesions develop according to characteristic, disease-specific sequences between highly interconnected regions of the brain in some AANDs (e.g. AD, tauopathies