Currently, there is no cure for Parkinson's disease. While there are some treatment options to manage the patients' symptoms, targeted molecular therapies are slow in coming. Our laboratory focuses on the understanding of the molecular basis of Parkinson's disease


Autosomal-dominantly inherited Parkinson's disease associated genes

Parkinson's disease (PD) has been classically considered an idiopathic disease. However, during the last two decades it has become evident that PD has an important genetic component. The first identified mutations that cause PD were found in α-synuclein gene (SNCA). The presence of the small synaptic α-synuclein proteins in the Lewy bodies - a typical pathological hallmark of  PD - indicates an intimate relationship between the inherited and the more common non-genetic forms of the disease. 

In 2004, the identification of mutations in another gene called LRRK2 had a significant impact on the PD field.  This is due to the prevalence of LRRK2 mutations in many PD cases across the globe. Moreover, LRRK2 is of particular interest for researchers not only because of its prevalence, but also because of the nature of LRRK2 PD. Clinical manifestation of LRRK2 PD is generally indistinguishable from the most common non-genetic PD. Unlike previously identified genes linked to PD that cause early-onset forms of the disease, LRRK2 mutations cause late onset typical PD.  

Importantly, genome-wide association studies demonstrated that the same genes involved in the autosomal-dominantly inherited forms of PD such as SNCA and LRRK2 can act as risk factors in sporadic PD. As such, the knowledge of how SNCA and LRRK2 mutations impact cellular processes can provide mechanistic insights into understanding the pathophysiological basis of sporadic PD.


Previous Findings

  • LRRK2 directs neuronal cytoskeletal dynamics 
  • LRRK2 and α-synuclein act synergistically in the molecular and cellular events that underlie PD
  • An emerging role of LRRK2 at the synapse 

LRRK2 and α-synuclein interplay: Co-expression of the pathogenic G2019S mutation leads to increased mitochondrial fragmentation in A53T/G2019S neurons (F). Arrows indicate normal mitochondrial appearance. The abnormal accumulation of somatic α-synuclein in the A53T/G2019S correlates with the degree of mitochondrial fragmentation. Neurons displaying somatic α-synuclein accumulation are shown with asterisk. LinX*, Parisiadou L*. et. al., Neuron 2009


LRRK2 directs neuronal cytoskeletal dynamics: Developing neurons derived from G2019S mice displayed shorter neurites, and increased F-actin content in their filopodia compared to neurons from control; littermates. Parisiadou L. et. al, Journal of Neuroscience, 2009

LRRK2 and α-synuclein interplay: Coexpression of G2019S  accelerated neurodegeneration in A53T/G2019S brains compared to single transgenic ones. LinX*, Parisiadou L*. et. al., Neuron 2009


LRRK2 at the synapse. A. LRRK2 is strategically located in the dendritic shaft to organize signaling events in a spatiotemporal way. B. LRRK2 determines dendritic spine morphology of striatal projection neurons. C. LRRK2 directs synaptic transmission in striatal projection neurons. Parisiadou L. et. al, Nature Neuroscience, 2014.


Provided the importance of LRRK2 in both familial and sporadic PD, it is reasonable to argue that knowledge on the normal function of the encoded protein can help us understand the disease process. To a step further, modulation of its dysfunction in the disease content would be a way to intervene in PD more broadly. Genetic studies in neurodegenerative diseases tend to identify gene products with minimal potential for traditional therapeutic interventions. The LRRK2 protein combining a GTPase known as a Ras of complex (ROC) domain, with a kinase domain (Figure 1), makes a very powerful combination for a drug target. As such, our major scientific efforts are focused to understand the physiological role of LRRK2, as well its dysfunction in the disease content. 

Figure 1: LRRK2 domains and pathogenic mutations. LRRK2 is a large, and multi-domain protein. Its central enzymatic region consists of a GTPase Ras of complex (ROC domain), a C-terminal of Roc domain (COR), and a kinase domain. Different protein-protein interaction domains surround the enzymatic core. The pathogenic mutations that definitively cause PD are restricted to the central catalytic region of LRRK2.


  • LRRK2 mediated cellular and molecular events in the striatum
  • Looking for novel therapeutic approaches for LRRK2 mediated PD: the identification of novel LRRK2 modifiers in specific sub-neuronal populations.
  • Unraveling the mechanistic details of α-synculein clearance.

In order to achieve those research goals, the laboratory employs a multidisciplinary approach spanning cellular, network and behavioral levels in a number of model systems.

Although there is a long way to completely understand the etiology and pathophysiological basis of PD, the study of α-synuclein, and LRRK2 has provided useful insights into this process, as well as the molecular tools to possibly develop mechanistic based therapeutic opportunities for a disease that is currently addressed symptomatically.