Protein aggregate spreading in neurodegenerative diseases: problems and perspectives

Abstract

Progressive accumulation of specific protein aggregates is a defining feature of many major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, fronto-temporal dementia, Huntington's disease, and Creutzfeldt-Jakob disease (CJD). Findings from several recent studies have suggested that aggregation-prone proteins, such as tau, α-synuclein, polyglutamine-containing proteins, and amyloid-β, can spread to other cells and brain regions, a phenomenon considered unique to prion disorders, such as CJD and bovine spongiform encephalopathy. Cell-to-cell propagation of protein aggregates may be the general underlying principle for progressive deterioration of neurodegenerative diseases. This may also have significant implications in cell replacement therapies, as evidenced by the propagation of α-synuclein aggregates from host to grafted cells in long-term transplants in Parkinson's patients. Here, we review recent progress in protein aggregate propagation in experimental model systems and discuss outstanding questions and future perspectives. Understanding the mechanisms of this pathological spreading may open the way to unique opportunities for development of diagnostic techniques and novel therapies for protein misfolding-associated neurodegenerative diseases.

Fig. 1

Amyloidogenic protein aggregation process. Graph shows kinetics of amyloidogenesis. Black trace represents the general “uninduced” amyloidogenesis, while red trace represents the amyloidogenesis upon “seeding” with preformed aggregates. Process of amyloidogenesis involves several intermediate species, including dimmers, small oligomers, and protofibrils, some of which may have stability and conformational properties for serving as “nucleus” (scheme underneath the black trace). When preformed amyloids are present, these intermediate steps, hence the nucleation steps, are bypassed; monomers are directly recruited to amyloids (scheme above the red trace). Globular oligomers refer to broardly defined oligomeric aggregates, which may include both unstable “pre-nuclear” intermediates and relatively stable intermediates with the characteristics of nucleus. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

Fig. 2

Potential mechanisms of protein aggregation induced by aggregates originated from neighboring neurons. The model depicts how protein aggregates originated from one neuron (neuron 1) might induce protein aggregation in another neuron (neuron 2).