Parkinson's disease (PD) is the second most common neurodegenerative disease in the world, generating progressive debilitations to the patient, such as motor impairment, cognitive and psychiatric deficits. Of all registered cases of the disease, only 10% are familial whereas 90% of them are of unknown causes, that is, idiopathic (iPD). Despite intensive research, attempts to stop or even slow the progression of PD have failed so far. Although most PD cases are idiopathic and have a widely unknown etiology, mutations in ~ 20 genes, including LRRK2 (leucine-rich repeat kinase 2), cause rare genetic parkinsonism. All the pathogenic mutations in LRRK2 result in hyperactivation of the LRRK2 kinase, thereby being a suitable target for designing therapeutical strategies. In addition, natural genetic variations leading to an increase in the phosphorylation activity of LRRK2 is a risk factor for the development of PD, but the exact role of LRRK2 in this pathology is still not fully understood. Recent advances point LRRK2 as having a key role in the regulation of autophagy through phosphorylation of a subgroup of proteins called Rabs-GTPases and regulates their ability to bind to cognate effector proteins. The main function of Rab proteins is to control membrane delivery and sorting of membrane derived vesicles in the cell. Among the LRRK2-mediated phosphorylated Rabs, is Rab10, which has been implicated in the maintenance of the endoplasmic reticulum, vesicle trafficking and autophagy. LRRK2-induced phosphorylation of Rab10 inhibits its function by preventing the GDP dissociation, a necessary event for the distribution and recycling of the membrane. Thus, aberrantly increased LRRK2 kinase activity is probably associated with the reduced activity of Rab10 and its effectors, allowing the accumulation of neuronal cytoplasmic aggregates, such as the protein involved in PD, ±-synuclein. However, in addition to Rab 10, it is described that LRRK2 potentially mediates phosphorylation in the following Rabs: Rab 1a, 1b, 3c, 8a, 8b and 35, although the consequences for those phosphorylations are unknown. In neurons membrane delivery is essential to define subcellular domains and control most of their physiological functions. Here, we propose to evaluate the consequences of LRRK2 abnormal activity associated to iPD using in vitro and in vivo approaches. We will address how the activity of LRRK2 modify both Rab-mediated autophagy and membrane traffic dynamics and how these events could lead to dopaminergic neuronal death. Overall, these efforts will provide a link from the very basic cell biology of neurons to a translational future research. (AU)
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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FONSECA, MATHEUS DE CASTRO;
DE OLIVEIRA, JULIANA FERREIRA;
SILVA ARAUJO, BRUNO HENRIQUE;
VITAL DO PRADO, PAULA FAVORETTI;
AMORIM NETO, DIONISIO PEDRO;
BOSQUE, BEATRIZ PELEGRINI;
RODRIGUES, PAULLA VIEIRA;
PEREIRA DE GODOY, JOAO VITOR;
RIBEIRO FILHO, HELDER VERAS;
ZIEM NASCIMENTO, ANDREY FABRICIO;
COSTA TONOLI, CELISA CALDANA;
HELENO BATISTA, FERNANDA APARECIDA;
LOPES DE OLIVEIRA, PAULO SERGIO;
FIGUEIRA, ANA CAROLINA;
DA COSTA, SILVIA SOUZA;
VICTORINO KREPISCHI, ANA CRISTINA;
WESTFAHL, JR., HARRY;
ROQUE DA SILVA, ANTONIO JOSE;
FRANCHINI, KLEBER GOMES.
Molecular and cellular basis of hyperassembly and protein aggregation driven by a rare pathogenic mutation in DDX3X.
AUG 20 2021.
Web of Science Citations: 0.