| Περίληψη: | Several lines of evidence indicate that the propagation of misfolded α-synuclein (α-syn) plays a fundamental role in the initiation and progression of Parkinson’s disease (PD). Considering that the cell-to-cell transfer of misfolded α-syn entails its release accompanied by internalization, focusing on α-syn clearance in the extracellular space may be critical for preventing α-syn propagation and hence, slowing or even halting disease progression. Kallikrein-related peptidase 6 (KLK6), a serine protease primarily expressed in the CNS, has been suggested to play a crucial part in the proteolysis of intracellular α-syn. Although KLK6 is normally secreted and exhibits its enzymatic activity in the extracellular space, the capacity of this enzyme to degrade extracellular forms of α-syn still remains elusive. In the current study, we aim to decipher whether KLK6 plays a physiological role in regulating the turnover of naturally-secreted α-syn in the brain and whether it can be used as a therapeutic target for the elimination of misfolded/accumulated α-syn forms observed under pathological conditions.
Here, we demonstrate that both the recombinant and cell-secreted forms of KLK6 are able to degrade not only naturally-secreted α-syn but also pathogenic fibrilar α-syn forms. By utilizing Klk6 knockout (Klk6-/-) mice as our experimental model we show that behaviorally, Klk6-/- mice display intact motor and cognitive functions. Further in vivo characterization of this novel mouse model, in terms of α-syn accumulation, showed that KLK6 deletion had no impact on the protein levels of endogenous α-syn, either intracellularly or extracellularly. Upon in vivo administration of α-syn pre-formed fibrils (PFFs), no exacerbation of α-syn pathology was evident in the brains of Klk6-/- mice; while, exogenous delivery of KLK6 did not affect secreted α-syn levels observed in the PD mouse model of human A53T α-syn over-expression.
Our results clearly demonstrate that Klk6-/- mice do not develop a major neurodegenerative phenotype in response to KLK6 deletion; while, no predominant KLK6 regulatory effects on α-syn levels were prevalent, either under physiological or pathophysiological-relevant conditions. These novel findings suggest that in vivo, KLK6 is not a key-modulator of the α-syn turnover, possibly due to the presence of other compensatory proteolytic mechanisms, and further highlight the need of elucidating the role of this enzyme in an in vivo setting in order to employ KLK6 for future disease intervention.
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