Cathepsin D is a lysosomal protease important for clearance of long-lived proteins. Alpha-synuclein aggregation is a cardinal pathologic feature of PD. Alpha-synuclein gene amplification can cause PD. Without alpha-synuclein, neurons that produce the critical neurotransmitter, dopamine, can survive MPTP induced damage. We recently found that neurons without cathepsin D accumulate alpha-synuclein. We will examine whether reduction of cathepsin increases propensity of alpha-synuclein aggregation and whether delivering cathepsin D to dopaminergic neurons can make them resistant to toxin induced cell death.
Specific Aim 1: Determine whether knockout of cathepsin D enhances the vulnerability of dopaminergic neurons in whole animal pre-clinical models of PD. We will examine the effect of reduction of cathepsin D in susceptibility to MPTP and AAV-syn induced neurodegeneration. Specific Aim 2: Determine wheter cathepsin D delivered by viral vector are protective in whole animal pre-clinical models of PD. We will examine the effect of augmentation of cathepsin D in protection against MPTP-induced neurodegeneration.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Alpha-synuclein accumulation and aggregation are hallmarks of both inherited and sporadic forms of PD. There is little evidence for alpha-synuclein overproduction in sporadic PD, suggesting that impaired clearance plays a crucial role. Neurons without alpha-synuclein are resistant to toxin induced degeneration. Thus clearing alpha-synuclein may be an effective approach to prolong neuron survival. Validation of cathepsin D as a target for PD therapy may provide foundation for using the level and activities of cathepsin D as an indicator for propensity to PD pathogenesis. Enhancing cathepsin D function either by gene and protein delivery or by allosteric chemical enhancement may provide an effective therapy.
We will learn whether the levels and activities of cathepsin D can be further developed as an indicator for propensity to PD pathogenesis or as a diagnosis tool in humans. We will also learn whether enhancing cathepsin D can clear alpha-synuclein and/or be neuroprotective in mammalian PD models.
Dr. Zhang did not observe enhanced susceptibility to the acute and sub-acute treatment of toxin MPTP in mice with half the levels of cathepsin D. While the team aimed to determine whether greater susceptibility would be seen in a virally delivered alpha-synuclein model, these studies were delayed due to technical challenges with the model.
Continuing work is required to determine susceptibility to chronic MPTP in models deficient in cathepsin D, as well as in alpha-synuclein transgenic models, and to conclusively assess cathepsin D's true potential as a target for PD therapeutic development.