%0 Journal Article
%T A Link between Autophagy and the Pathophysiology of LRRK2 in Parkinson's Disease
%A Patricia G¨®mez-Suaga
%A Elena Fdez
%A Marian Blanca Ram¨ªrez
%A Sabine Hilfiker
%J Parkinson's Disease
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/324521
%X Parkinson's disease is a debilitating neurodegenerative disorder, and its molecular etiopathogenesis remains poorly understood. The discovery of monogenic forms has significantly advanced our understanding of the molecular mechanisms underlying PD, as it allows generation of cellular and animal models carrying the mutant gene to define pathological pathways. Mutations in leucine-rich repeat kinase 2 (LRRK2) cause dominantly inherited PD, and variations increase risk, indicating that LRRK2 is an important player in both genetic and sporadic forms of the disease. G2019S, the most prominent pathogenic mutation, maps to the kinase domain and enhances enzymatic activity of LRRK2, which in turn seems to correlate with cytotoxicity. Since kinases are druggable targets, this has raised great hopes that disease-modifying therapies may be developed around modifying LRRK2 enzymatic activity. Apart from cytotoxicity, changes in autophagy have been consistently reported in the context of G2019S mutant LRRK2. Here, we will discuss current knowledge about mechanism(s) by which mutant LRRK2 may regulate autophagy, which highlights additional putative therapeutic targets. 1. Introduction Parkinson¡¯s disease (PD) is a common neurodegenerative disorder with symptoms including tremor, rigidity, and postural instability [1]. Autosomal-dominant mutations in leucine-rich repeat kinase 2 (LRRK2) comprise the most common monogenic form of PD [2¨C5]. LRRK2-associated PD is symptomatically and neurochemically largely indistinguishable from sporadic PD cases [6], even though the reported pleomorphic pathology of mutant LRRK2 carriers differs from the rather classical ¦Á-synuclein pathology associated with sporadic PD. Variations in LRRK2 have further been reported to increase risk for sporadic PD [7¨C9], which implicates LRRK2 in both sporadic and familial forms of the disease. The big advantage of studying the function of a mutated gene product as compared to a sporadic disease is that one can generate cellular and animal models carrying the mutant gene to define pathological pathways. In conjunction with the described enzymatic activity of LRRK2 which may be targeted by select kinase inhibitors [10, 11], this has propelled the protein into the limelight of PD research worldwide. However, to develop disease-modifying or neuroprotective therapies around LRRK2, a clear understanding of its normal and pathological function(s) is required. A link between LRRK2 and aberrant macroautophagy has been consistently observed, and here we review our current knowledge of LRRK2¡¯s role in
%U http://www.hindawi.com/journals/pd/2012/324521/