The therapeutic potential of lysosomal cathepsins D, B and L (CTSD, CTSB and CTSL) on alpha-synuclein pathology and Parkinson Disease

Neurons are particularly vulnerable to alterations in cellular proteostasis, mainly due to their inability to dilute substrate accumulation by mitosis. It is therefore not surprising that lysosomal dysfunction underlies pathologies featuring protein aggregation, such as Neuronal Ceroid Lipofuscinosis (NCL) and Parkinson disease (PD). Given that several aggregation-prone proteins including alpha-synuclein (SNCA) are known substrates of lysosomal cathepsins D, B and L (CTSD, CTSB and CTSL), the activity of these proteases may be vital to maintaining neuronal health.

The first part of this thesis analyzed the impact of previously identified neurodegenerative-associated point mutations within CTSD on protein function. It was revealed that NCL-associated CTSD variants disrupt its protein maturation, possibly explaning the severe phenotype that characterizes this disease. 

The second and main part of this study demonstrated that enhancing CTSD, CTSB and CTSL via enzyme replacement therapy boost SNCA clearance. Increasing protein levels of lysosomal cathepsins resulted in a significant reduction of SNCA aggregation in induced pluripotent stem dopaminergic neurons derived from PD patients and an alpha-synucleinopathy mouse model. Moreover, enhancement of CTSD resulted in the restoration of synaptic markers in vitro, suggesting that neuronal function could be rescued.

Altogether, this study reveals that targeting lysosomal function of CTSD, CTSB and CTSL could serve as a therapeutic strategy for SNCA pathology.


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