Leucine-rich repeat kinase 2 (LRRK2), also known as dardarin (from the Basque word "dardara" which means trembling) and PARK8 (from early identified association with Parkinson's disease), is a large, multifunctional kinase enzyme that in humans is encoded by the LRRK2 gene. [5] [6] LRRK2 is a member of the leucine-rich repeat kinase family. Variants of this gene are associated with an increased risk of Parkinson's disease and Crohn's disease. [5] [6]
The LRRK2 gene encodes a protein with an armadillo repeats (ARM) region, an ankyrin repeat (ANK) region, a leucine-rich repeat (LRR) domain, a kinase domain, a RAS domain, a GTPase domain, and a WD40 domain. The protein is present largely in the cytoplasm but also associates with the mitochondrial outer membrane.
LRRK2 interacts with the C-terminal R2 RING finger domain of parkin, and parkin interacted with the COR domain of LRRK2. Expression of mutant LRRK2 induced apoptotic cell death in neuroblastoma cells and in mouse cortical neurons. [7]
Expression of LRRK2 mutants implicated in autosomal dominant Parkinson's disease causes shortening and simplification of the dendritic tree in vivo and in cultured neurons. [8] This is mediated in part by alterations in macroautophagy, [9] [10] [11] [12] [13] and can be prevented by protein kinase A regulation of the autophagy protein LC3. [14] The G2019S and R1441C mutations elicit post-synaptic calcium imbalance, leading to excess mitochondrial clearance from dendrites by mitophagy. [15] LRRK2 is also a substrate for chaperone-mediated autophagy. [16]
Disease-associated mutant alleles of LRRK2 (R1441C, G2019S, I2020T) generally show elevated kinase activity. [17] [18]
LRRK2 activity has been tied to generation of reactive-oxygen species (ROS) which are associated with Parkinson's disease pathogenesis. This activity is dependent on LRRK2-mediated phosphorylation of NADPH oxidase 2 (NOX2). Specifically, LRRK2 activity promotes activatory phosphorylation of the p47phox subunit of NOX2 at S345. [19]
Mutations in this gene have been associated with Parkinson's disease type 8. [20] [21]
The G2019S mutation results in enhanced kinase activity, and is a relatively common cause of familial Parkinson's disease in Caucasians. [22] It may also cause sporadic Parkinson's disease. The mutated Gly amino acid is conserved in all kinase domains of all species.
The G2019S mutation is one of a small number of LRRK2 mutations proven to cause Parkinson's disease. Of these, G2019S is the most common in the Western World, accounting for ~2% of all Parkinson's disease cases in North American Caucasians. This mutation is enriched in certain populations, being found in approximately 20% of all Ashkenazi Jewish Parkinson's disease patients and in approximately 40% of all Parkinson's disease patients of North African Berber Arab ancestry. [23] [24]
Unexpectedly, genome-wide association studies have found an association between LRRK2 and Crohn's disease as well as with Parkinson's disease, suggesting that the two diseases share common pathways. [25] [26]
Attempts have been made to grow crystals of the LRRK2 aboard the International Space Station, as the low-gravity environment renders the protein less susceptible to sedimentation and convection, and thus more crystallizable. [27]
Mutations in the LRRK2 gene is the main factor in contributing to the genetic development of Parkinson's disease, and over 100 mutations in this gene have been shown to increase the chance of PD development. These mutations are most commonly seen in North African Arab Berber, Chinese, and Japanese populations. [28]
Multiple preclinical studies have found that inhibition or silencing of LRRK2 may be therapeutically beneficial for treatment of Parkinson's disease. [29] [30] There have been efforts to develop therapeutics for Parkinson's disease targeting LRRK2, including LRRK2 inhibitors [31] [32] and antisense oligonucleotides (ASOs) targeting LRRK2. [33]
Alpha-synuclein (aSyn) is a protein that, in humans, is encoded by the SNCA gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release.
CREB-TF is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first described in 1987 as a cAMP-responsive transcription factor regulating the somatostatin gene.
Ubiquitin carboxy-terminal hydrolase L1 is a deubiquitinating enzyme.
Parkin is a 465-amino acid residue E3 ubiquitin ligase, a protein that in humans and mice is encoded by the PARK2 gene. Parkin plays a critical role in ubiquitination – the process whereby molecules are covalently labelled with ubiquitin (Ub) and directed towards degradation in proteasomes or lysosomes. Ubiquitination involves the sequential action of three enzymes. First, an E1 ubiquitin-activating enzyme binds to inactive Ub in eukaryotic cells via a thioester bond and mobilises it in an ATP-dependent process. Ub is then transferred to an E2 ubiquitin-conjugating enzyme before being conjugated to the target protein via an E3 ubiquitin ligase. There exists a multitude of E3 ligases, which differ in structure and substrate specificity to allow selective targeting of proteins to intracellular degradation.
The tau proteins form a group of six highly soluble protein isoforms produced by alternative splicing from the gene MAPT. They have roles primarily in maintaining the stability of microtubules in axons and are abundant in the neurons of the central nervous system (CNS), where the cerebral cortex has the highest abundance. They are less common elsewhere but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.
A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic.Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.
Gamma-synuclein is a protein that in humans is encoded by the SNCG gene.
Vacuolar protein sorting ortholog 35 (VPS35) is a protein involved in autophagy and is implicated in neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). VPS35 is part of a complex called the retromer, which is responsible for transporting select cargo proteins between vesicular structures and the Golgi apparatus. Mutations in the VPS35 gene (VPS35) cause aberrant autophagy, where cargo proteins fail to be transported and dysfunctional or unnecessary proteins fail to be degraded. There are numerous pathways affected by altered VPS35 levels and activity, which have clinical significance in neurodegeneration. There is therapeutic relevance for VPS35, as interventions aimed at correcting VPS35 function are in speculation.
Leucine-rich repeat serine/threonine-protein kinase 1 is an enzyme that in humans is encoded by the LRRK1 gene.
Leucine-rich repeat and Immunoglobulin-like domain-containing protein 1 also known as LINGO-1 is a protein which is encoded by the LINGO1 gene in humans. It belongs to the family of leucine-rich repeat proteins which are known for playing key roles in the biology of the central nervous system. LINGO-1 is a functional component of the Nogo receptor also known as the reticulon 4 receptor.
Parkinson's disease (PD) is a complicated neurodegenerative disease that progresses over time and is marked by bradykinesia, tremor, and stiffness. As the condition worsens, some patients may also experience postural instability. Parkinson's disease (PD) is primarily caused by the gradual degeneration of dopaminergic neurons in the region known as the substantia nigra along with other monoaminergic cell groups throughout the brainstem, increased activation of microglia, and the build-up of Lewy bodies and Lewy neurites, which are proteins found in surviving dopaminergic neurons.
Leucine rich repeat and Ig domain containing 2 is a protein that in humans is encoded by the LINGO2 gene.
The pathophysiology of Parkinson's disease is death of dopaminergic neurons as a result of changes in biological activity in the brain with respect to Parkinson's disease (PD). There are several proposed mechanisms for neuronal death in PD; however, not all of them are well understood. Five proposed major mechanisms for neuronal death in Parkinson's Disease include protein aggregation in Lewy bodies, disruption of autophagy, changes in cell metabolism or mitochondrial function, neuroinflammation, and blood–brain barrier (BBB) breakdown resulting in vascular leakiness.
Ted M. Dawson is an American neurologist and neuroscientist. He is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases and Director of the Institute for Cell Engineering at Johns Hopkins University School of Medicine. He has joint appointments in the Department of Neurology, Neuroscience and Department of Pharmacology and Molecular Sciences.
Valina L. Dawson is an American neuroscientist who is the director of the Programs in Neuroregeneration and Stem Cells at the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. She has joint appointments in the Department of Neurology, Neuroscience and Physiology. She is a member of the Graduate Program in Cellular and Molecular Medicine and Biochemistry, Cellular and Molecular Biology.
Animal models of Parkinson's disease are essential in the research field and widely used to study Parkinson's disease. Parkinson's disease is a neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The loss of the dopamine neurons in the brain, results in motor dysfunction, ultimately causing the four cardinal symptoms of PD: tremor, rigidity, postural instability, and bradykinesia. It is the second most prevalent neurodegenerative disease, following Alzheimer's disease. It is estimated that nearly one million people could be living with PD in the United States.
Rubicon is a protein that in humans is encoded by the RUBCN gene. Rubicon is one of the few known negative regulators of autophagy, a cellular process that degrades unnecessary or damaged cellular components. Rubicon is recruited to its sites of action through interaction with the small GTPase Rab7, and impairs the autophagosome-lysosome fusion step of autophagy through inhibition of PI3KC3-C2.
Dimitri Krainc is a Slovenian-born American physician-scientist who is the Aaron Montgomery Ward Professor and Chairman of the Ken & Ruth Davee Department of Neurology and Director of the Feinberg Neuroscience Institute and the Simpson Querrey Center for Neurogenetics at Northwestern University Feinberg School of Medicine. After completing his medical training at the University of Zagreb, Krainc spent more than two decades at the Massachusetts General Hospital and Harvard Medical School, where he completed his research and clinical training and served on faculty until relocating to Northwestern University in 2013. He has dedicated his scientific career to studying molecular pathways in the pathogenesis of neurodegeneration. Informed by genetic causes of disease, his work has uncovered key mechanisms across different neurodegenerative disorders that have led to pioneering design and development of targeted therapies. He has received numerous awards and recognitions for his work, including the Javits Neuroscience Investigator Award and the Outstanding Investigator award from NIH, and was elected to the Association of American Physicians, the National Academy of Medicine, the National Academy of Inventors and the Croatian Academy of Sciences and Arts He is the principal founding scientist of two biotech companies and serves as Venture Partner at OrbiMed. Krainc is President-elect of the American Neurological Association.
Epidemiological studies have shown lower age-related prevalence of Parkinson's disease in South Asians, with the rate of prevalence being around 52.7 per 100,000 as compared to a higher prevalence rate observed in populations with European origin, 108-257 per 100,000. Additionally, several studies have seen a higher prevalence of in women which contrasts with global data that observes a overall higher prevalence seen in men. Compared to most of the rest of the world, the South Asian countries seem to be on the lower end of PD prevalence. However, this is not to say that PD is not of concern in these countries. Over the past couple of years, the rate of Parkinson's has gone up in South Asia meaning that it is of high importance to study this pathological disease in these populations.
Zhenyu Yue is a Chinese academic researcher in the field of neurology and neuroscience, who is the Alex and Shirley Aidekman Professor at the Icahn School of Medicine at Mount Sinai, New York. He is known for his discovery of genes controlling autophagy, autophagy functions in central nervous system, molecular mechanism of neurodegenerative diseases, and modelling neurological diseases using genetic mouse models.
A collaboration between the Michael J. Fox Foundation, of New York City, and Merck Research Laboratories, of Kenilworth, New Jersey, will seek to grow crystals of a key gene protein, Leucine-Rich Repeat Kinase 2 (LRRK2), in an effort to advance the search for a cure for Parkinson's disease. Crystals cultured in the absence of gravity are less susceptible to sedimentation and convection, rendering them larger and easier to map than those grown in labs on Earth in order to design medicines.
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