The pathways of a-synuclein degradation are still subject to debate. Some research suggests that it can be degraded by either autophagy or the proteasome (16). It can also be degraded by proteases, a few of which have been identified: Kallikrein-6 (KLK6) and calpain-1 (CALN1) are the two main proteases that degrade a-synuclein. KLK6 is a serine protease expressed abundantly in the brain, in particular neurons and oligodendrocytes, which are both potential areas of a-synuclein aggregation. Its degrading activity has been explored in vitro, where it has been found to cleave monomeric a-synuclein and is predicted to protect against aggregation by reducing monomeric a-synuclein levels. CALN1 is expressed in neurons and presynaptic terminals, where it’s proposed to interact with a-synuclein. CALN1 cleaves fibrillar as well as monomer forms of a-synuclein. Cleavage of fibrillar forms is believed to promote aggregation and neurotoxicity of aggregated a-synuclein. Thus, there is some debate as to the role of CALN1 in potentially promoting aggregates. However, a recent study found that reduction in CALN1 activity led to an increase in phosphorylated serine-129, which is the form found in a-synuclein aggregates (17). This seems to indicate that CALN1 does not play a role in aggregation.
Researchers propose that a reduction in these enzymes contributes to the accumulation of a-synuclein in Lewy body diseases (17). In support of this hypothesis, post mortem brain analysis reveals decrease in the concentration of KLK6 and CLN1. Additionally, accumulation of a-synuclein is inversely proportional to levels of KLK6 and CLIN1. Furthermore, a knockdown of the enzymes resulted in increase of the amount of a-synuclein in cell lysate (17).
Figure 1. The authors found that in the control, a-synuclein was able to propagate and accumulate in astroglial cells. However, when they treated the animals with a neurosin lentiviral vector, extracellular a-synuclein was significantly decreased. Image source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580347/
Researchers found that lentiviral vector delivery of neurosin (kallikrein-6) to the brain of mouse model for dementia with Lewy bodies reduced the accumulation of a-synuclein and improves neuronal synapse function (18). The authors of the study used neurosin with addition of an LDL-R binding domain of apolipoprotein B, which enabled them to target the protein for transport across the blood brain barrier (BBB). In addition, it also targets the protein for uptake by cells expressing LDL-R, which include neurons and to a smaller extend oligodendrocytes. In the study, the model a-synuclein was only expressed in oligodendroglial cells. The researchers found that a-synuclein was most successfully cleared by microglial cells, similarly to how microglial cells clear amyloid beta in Alzheimer’s disease.
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