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  • Autophagy alterations are frequently reported as one of the

    2021-01-13

    Autophagy alterations are frequently reported as one of the pathological mechanisms contributing to neurodegenerative diseases, due to incomplete removal of protein beta lactamase inhibitor in the brain [30,41]. It was over a decade ago when mutations in PARK8 encoding for the LRRK2 protein were described as a main genetic determinant for autosomal dominant Parkinson's disease (PD) [42,43]. PD is a neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and also by formation of Lewy bodies containing beta lactamase inhibitor α-synuclein deposits [20]. Currently mutations in about 20 genes have been identified in association with PD [44]. LRRK2 is the gene most frequently mutated in familial PD and these mutations are located within the enzymatic core of the protein, the ROC/COR or kinase domains [44,45]. Moreover, LRRK2 forms also a risk for sporadic PD forms [45]. Polymorphisms of LRRK2 determining its involvements in sporadic PD are however located in the promotor region of LRRK2, which highlights the possibility that changes in expression levels of LRRK2 may contribute to PD hallmarks in addition to activity changes corresponding to the mutations within the enzymatic core [45]. Despite intensive research in the field, the exact role of LRRK2 in PD has not yet been fully elucidated. The best studied and the most common LRRK2 mutations in PD include G2019S in the kinase domain as well as the R1441C/G/H and Y1699C mutations within the GTPase ROC/COR domains [44]. Considering that many of the LRRK2 mutants display altered enzymatic activities [44] and that LRRK2 kinase activity was enhanced in idiopathic PD irrespectively of LRRK2 mutations [46], efforts have been made towards development of kinase inhibitors. That seems to be a promising therapeutic approach since multiple studies showed that individuals carrying mutations such as G2019S are likely to develop PD symptoms over time [47]. Surprisingly, however, G2019S overexpression models of LRRK2 mice do not show pathological hallmarks in the brain [19]. Among other pathological conditions connected to LRRK2 function is Crohn's disease. This autoimmune syndrome is characterized by inflammation of the colon tissue and correlates with elevated levels of LRRK2 in patient samples [16]. LRRK2 was also shown to stimulate NF-κB-dependent pathways and to be a downstream target of interferon-γ [16] while enhanced LRRK2 phosphorylation was found in response to Toll-like receptors stimulation, stressing the importance of LRRK2 in response to pathogens [15]. In turn, polymorphisms in DAPK1 correlate with late onset of Alzheimer's disease [48] and DAPK was also shown to be involved in neurodegeneration and related tau toxicity in the Drosophila model [49]. The disease most associated with DAPK1 however, is cancer. The loss of DAPK1 was observed in many tumors and its expression levels correlates with tumor progression and survival prognosis due to tumor growth control via autophagy [2,18,50].
    Structure-function of ROCO kinases Apart from the catalytic domains, namely the kinase domain and the ROC/COR GTPase domains, ROCO kinases contain several other domains and motifs (Fig. 1). LRRK1 and LRRK2 share many similarities in structure as they both possess ankyrin-like (Ank) repeats, followed by the leucine-rich repeat (LRR) motif. In addition, LRRK2, but neither LRRK1 nor DAPK1, contains an Armadillo (Arm) domain at its N-terminus and a WD40 domain at its C-terminus. The structure of DAPK1 is enriched with a Ca2+/calmodulin (CaM) autoregulatory domain between the kinase domain and the ROC/COR domains and with a death domain at its C-terminus, while DAPK2 is basically limited to its kinase domain followed by a Ca2+/CaM autoregulatory domain (Fig. 1) [3,51,52]. The function of all these domains and motifs is not fully understood yet, although the evidence is growing that they contribute to ROCO proteins activity by enabling conformational changes, protein-protein interactions and signal transduction leading to their specific roles in cellular processes.