Age-related misfolding and aggregation of disease-linked proteins in selective brain regions is a characteristic of neurodegenerative diseases. Although neuropathological aggregates that characterize these various diseases are found at sites other than synapses, increasing evidence supports the idea that synapses are where the pathogenesis begins. Understanding these diseases is hampered by our lack of knowledge of what the normal functions of these proteins are and how they are affected by aging. Evidence has supported the idea that neurodegenerative disease-linked proteins have a common propensity for prion protein-like cell-to-cell propagation. However, it is not thought that the prion-like quality of these proteins/peptides that allows their cell-to-cell transmission implies a role for human-to-human spread in common age-related neurodegenerative diseases. It will be important to better understand the molecular and cellular mechanisms governing the role of these aggregating proteins in neural function, especially at synapses, how their propagation occurs and how pathogenesis is promoted by aging. 1. Synapses The brain is particularly vulnerable to degenerative diseases of ageing. Aberrant aggregation of proteins/peptides is the common theme among these diseases. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common age-related neurodegenerative diseases, while other less common, albeit devastating, neurodegenerative diseases include Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), prion diseases, and frontotemporal dementia (FTD). Although the specific protein aggregates and selective cellular vulnerabilities differ, shared disease mechanisms are increasingly apparent among neurodegenerative diseases and next to aberrant protein aggregation also include anatomically selective cell-to-cell propagation. Major themes of research on these diseases have included therapeutic neurotransmitter replacement, most successful with dopamine for PD, elucidating the biology of aberrant protein misfolding, and trying to understand how ageing promotes the development of these diseases. More recently, synapses have moved more to the center of research on these diseases [1, 2]. Neurites (axons and dendrites) and synapses are a unique feature of neurons and play fundamental roles in brain function. Furthermore, the aggregation-prone proteins linked pathologically and genetically to neurodegenerative diseases are normally present particularly at synapses. For example, the PD-linked protein -synuclein is known to normally reside
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