A small number of proteins in the body and brain are known to become misfolded or altered in ways that provoke the formation of extensive, harmful protein aggregates. Neurodegenerative conditions in particular are strongly linked to the aggregates of specific proteins, such as amyloid-β, tau, and α-synuclein. Researchers continue to discover new proteins that produce aggregates capable of contributing significantly to forms of age-related disease, however. That TDP-43 aggregates to cause a prominent form of dementia is a comparatively recent discovery, for example. Further, research makes clear that many more proteins, potentially hundreds, can produce aggregates as a result of dysfunction in protein quality control mechanisms. Thus we should probably expect that the present body of knowledge is incomplete with regard to which proteins and aggregates are important in age-related disease.
Protein aggregation is a hallmark of neurodegenerative diseases and is also observed in the brains of elderly individuals without such conditions, suggesting that aging drives the accumulation of protein aggregates. However, the comprehensive understanding of age-dependent protein aggregates involved in brain aging remains unclear. Here, we investigated proteins that become sarkosyl-insoluble with age and identified hyaluronan and proteoglycan link protein 2 (HAPLN2), a hyaluronic acid-binding protein of the extracellular matrix at the nodes of Ranvier, as an age-dependent aggregating protein in mouse brains.
Elevated hyaluronic acid levels and impaired microglial function reduced the clearance of HAPLN2, leading to its accumulation. HAPLN2 oligomers induced microglial inflammatory responses both in vitro and in vivo. Furthermore, age-associated HAPLN2 aggregation was also observed in the human cerebellum. These findings suggest that HAPLN2 aggregation results from age-related decline in brain homeostasis and may exacerbate the brain environment by activating microglia. This study provides new insights into the mechanisms underlying cerebellar aging and highlights the role of HAPLN2 in age-associated changes in the brain.
Link: https://doi.org/10.1371/journal.pbio.3003006
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