Supervisors info:
Λεωνίδας Στεφανής, Καθηγητής, Ιατρική, ΕΚΠΑ
Κωνσταντίνος Βεκρέλλης, Ερευνητής Β΄, Ίδρυμα Ιατροβιολογικών Ερευνών Ακαδημίας Αθηνών
Παναγιώτης Πολίτης, Αναπληρωτής Καθηγητής, Τμήμα Χημείας, ΕΚΠΑ
Summary:
Parkinson’s disease (PD) is a devastating, movement disorder that affects approximately 1.8 % people over the age of 65 and 2.6 % in people over the age of 85 of the worldwide population. While PD creates a substantial psychological, social and economic burden, there is not yet a biological treatment in which the progression of PD is stopped. Although, the etiology of Parkinson's disease is not clearly known, there are genetic factors that stimulate the disease development. Our work is focused on the mechanisms of neurodegeneration associated with the most commonly mutated gene: leucine-rich repeat kinase 2 (LRRK2). Previous studies have identified multiple mechanisms by which mutant forms of LRRK2 can lead to neurodegeneration typical of PD; however, there is evidence that normal, wild type, LRRK2 also plays a role in PD pathogenesis linked to other forms of the disease, as well as idiopathic PD. Through its action in regulating inflammation and immune system signaling, LRRK2 may play a vital role in PD in general, including rare cases associated with mutations in the alpha-synuclein gene. LRRK2 inhibition, either genetically or by pharmacological inhibition of its kinase activity, suppresses microglial activation following exposure to TLR4-pathway agonists such as LPS and fibrillar alpha-synuclein. Until now, it is not clearly known if neuroinflammation, a characteristic feature of Parkinson’s disease pathology has a promoting or a protecting role in neuronal loss, as well as, the role of LRRK2 in immune signaling in this context. Endogenous phosphorylation substrates for the LRRK2 kinase, Rab GTPases, as Rab10 are implicated in exocytic mechanisms in neurons and other cell types. It has been shown that Rab10 facilitates Toll-like receptor-4 (TLR4) signaling by controlling its trafficking onto the plasma membrane. In this study, using Western immunoblotting and flow cytometry we test if the regulation of TLR4 and TLR2 trafficking by Rab10 is dependent on LRRK2 in RAW264.7 cells. As, the phosphorylation of Rab10 by LRRK2 inhibits its function, we predict that blocking this phosphorylation in our model would prevent the regulation of LPS- or PFF-induced TLR trafficking by Rab10. LRRK2 kinase inhibition blocks the loss of TLR at the membrane, effectively suppressing its recycling, although it is not clear if this is a direct regulation, or if kinases or Rab GTPases participate in this regulation.
Keywords:
Parkinson's Disease, PD, Neurobiology, Signaling, Neurobiology, Neurodegenerative disorder, Nervous system, Immune system, Macrophages
