Font Size:
Site Colors:
Accesskey
S - Skip navigation
1 - Home page
4 - Search
Accessibility Statement

Pathological role of calpain-mediated LRRK2 cleavage in Parkinson's disease

Mutations in LRRK2 cause Parkinson's disease (PD). LRRK2 mutations lead to increased kinase activity and toxicity. Calpains are Ca2+-dependent proteases that are activated in PD, but their main targets in PD remain unclear. Our results indicate that calpain cleaves LRRK2 in PD and that LRRK2 is more sensitive to calpain than ï¡-synuclein. We also found that LRRK2 cleavage leads to increased kinase activity and that LRRK2 disease-mutants are more susceptible to calpain cleavage than wild-type LRRK2, resulting in a greater enhancement of LRRK2 kinase activity. We hypothesize that calpain-mediated LRRK2 cleavage enhances LRRK2 kinase activity and contributes to a gain-of-function mechanism in PD. In Aim 1, we will evaluate the extent of LRRK2 cleavage in PD and other ï¡-synucleinopathy brains. We will also determine if LRRK2 cleavage is identified in CSF from PD patients and can be used as a marker for the disease. In Aim 2, we will determine if cleaved LRRK2 is toxic to neurons and its mechanisms of toxicity. We will also examine if ï¡-synuclein promotes LRRK2 cleavage and if they can play a role in neuronal toxicity in concert. In Aim 3, we will explore the effects of cleaved LRRK2 in vivo. We will determine if cleaved LRRK2 increases ï¡-synuclein pathology in PD models. Our project may uncover calpain-mediated LRRK2 cleavage as a new mechanism for toxicity in PD, and may help shed light on how LRRK2 increases

Name
Price
Quanity
Del.
Confirm and pay