Background and Significance
Parkinson’s disease (PD) is a neurological
disorder, chiefly characterized by early death of dopaminergic neurons in the
substantia nigra pars compacta (SNc) (Kalia & Lang, 2015), leading to bradykinesia, muscular rigidity, and rest tremor (Gibb & Lees, 1988). The onset of PD may precede diagnosis by years, making it
clinically challenging. This necessitates
greater understanding of PD pathogenesis for identification of potential gene
To this end, leucine-rich repeat kinase 2
(LRRK2) was identified as a causative gene for autosomal dominant familial PD (Zimprich et al., 2004). LRRK2
encodes a large 2527-amino acid protein comprising GTPase and kinase domains. LRRK2
is the most popular genetic cause of PD; the G2019S mutation alone accounts for up to 40% PD incidence in Ashkenazi
Jews (Healy et al., 2008).
LRRK2 is most abundant in the brain, the
kidney, and the immune system. From a biochemical standpoint, LRRK2 was shown
to be involved in a multitude of signaling pathways (Sánchez?Danés et al.,
2012). One of the first
identified pathways was the mitogen-activated protein kinase (MAPK) pathways,
where a G2019S-LRRK2 transgenic mouse
model showed degeneration of dopaminergic neurons in the SNc, analogous to human
PD (Chen et al., 2012).
Interestingly, very few studies are related
to identifying transcriptional factors that regulate expression of LRRK2. These
transcription factors may themselves be responsible for pathological phenotypes;
in any case, they provide novel entry points to further understand and modulate
the role of LRRK2 in various cellular processes.
A large variety of physiological functions is
associated with LRRK2: cytoskeleton formation, autophagy, vesicle dynamics, and
mitochondrial homeostasis (Wallings, Manzoni, & Bandopadhyay, 2015). At the same time, it also plays a pathological role in
neurodegeneration, unrelated inflammatory diseases, leprosy, and several types
of cancer (Bae & Lee, 2015). The resulting complex network of putative functions will greatly
inform specific treatment of PD and other diseases, but untangling this web is nearly
impossible. The identification of LRRK2 transcription factors and studies vis-à-vis
their activity and regulatory effects may inform PD treatment strategies and give
insight to the cell-specific organization of LRRK2 functions.