Parkinson Disease and LRRK2

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A link between Parkinson disease (PD) and mutations in the leucine-rich repeat kinase-2 gene LRRK2 was first discovered in the early 21st century . In 2002, Funayama and colleagues reported a large Japanese kindred with an autosomal-dominant form of PD that was linked to a novel genetic risk locus on chromosome 12. [1] This locus, designated as PARK8, was subsequently associated with familial PD in Caucasian families. In 2004, 2 groups simultaneously identified the genetic cause underlying PARK8-associated PD when they described mutations in LRRK2. [2, 3]

Since this discovery, a large number of novel LRRK2 mutations have been described as putative causes of PD. While it is likely that many of these are truly pathogenic mutations, proof of pathogenicity is difficult, and only 5 LRRK2 mutations (G2019S, R1441C, R1441G, I2020T, and Y1699C) are unequivocally linked to disease based on disease segregation in large families and functional studies. [4, 5, 6, 7]

Mutations in the catalytic Roc-COR and kinase domains of LRRK2 are considered common causes of familial PD. Cell and animal models of PD have indicated that LRRK2 mutations affect vesicular trafficking, autophagy, protein synthesis, and cytoskeletal function. LRRK2 mutations have been shown to cause PD with age-related penetrance and clinical features identical to late-onset sporadic PD. According to biochemical studies, there is an increase in LRRK2 kinase activity and a decrease in GTPase activity for kinase domain and Roc-COR mutations, respectively. [8]

One study demonstrated that LRRK2 regulates lysosome size, number, and function in astrocytes, which endogenously express high levels of LRRK2. Expression of LRRK2 G2019S produces enlarged lysosomes and diminishes the lysosomal capacity of these cells. Enlarged lysosomes were also observed with the LRRK2 mutations R1441C or Y1699C. According to the study, the lysosomal defects associated with these mutations are dependent on both the catalytic activity of the kinase and autophosphorylation of LRRK2 at serine 1292. [9]

Comprehensive mutation screening has shown that frequencies of LRRK2 mutations vary significantly across different ethnic groups. A good example is the G2019S mutation, the most common LRRK2 mutation in Caucasian populations. Within outbred Caucasian populations, this single change is believed to underlie approximately 5% of PD cases with a family history of PD and approximately 2% of apparently sporadic PD cases, [10, 11] thus for approximately half of all LRRK2 mutations in these populations.

In Ashkenazi Jewish communities, about 40% of familial and 13% of sporadic cases carry this mutation, and, in North African Berber Arabs, the frequency is even higher; specifically, 39% of familial cases and 40% of sporadic cases. In contrast, in Asian populations, this mutation is only rarely detected. [12, 13, 14, 15, 16] Of note, genetic data point toward a single founder for the vast majority of the G2019S PD cases. [17]

According to a research study by Inzelberg et al, dystonia due to a TOR1A gene mutation is responsible for most early-onset autosomal dominant dystonia, and 90% of Ashkenazi Jews who develop early-onset disease have TOR1A -related dystonia. The authors noted that familial Creutzfeldt-Jakob disease and cerebrotendinous xanthomatosis tend to cluster among Jews of North African descent, and Machado-Joseph disease is particularly frequent in Yemenite Jews. [18]

In addition to the above-mentioned disease-causing mutations characterized by segregation with disease in large families, there are 2 lines of evidence that support the idea that the LRRK2 locus also contains risk-modifying variants. The first line of evidence comes from studies within Asian populations showing that 2 protein-coding variants, G2385R and R1628P, increase the risk for PD approximately 2-fold; these mutations are present at a frequency of approximately 6% in cases, and approximately half that in controls. [19, 20]

The second line of evidence comes from genome-wide association studies that implicate noncoding variants close to LRRK2 with altered risk for PD and that suggest this risk may be mediated by altering the expression and/or splicing of LRRK2. [21]

The penetrance of LRRK2 mutations has been a topic of intense study and debate. The most parsimonious models employ age-based penetrance estimates, which suggest that the G2019S mutation has a penetrance of 28% at age 59 years, 51% at age 69 years, and 74% at age 79 years. For the R1441G change, a mutation with high prevalence in the Basque population, penetrance estimates are 13% at age 65 years, increasing to 83% at age 80 years. [22, 23] Penetrance estimates have not been established for other LRRK2 mutations.

Clinically, the presentation of typical LRRK2 -related PD is indistinguishable from idiopathic PD with late-onset, levodopa-responsive parkinsonism. In some cases, however, atypical features have been observed, including the following [2, 17, 24, 25] :

Early disease onset

Amyotrophy

Dementia

Hallucinations

Delusions

Dystonia of lower extremities

Variability also exists with respect to the neuropathology, ranging from Lewy body PD to nigral degeneration without distinctive histopathology, or tau-positive neurofibrillary tangle pathology. [2, 26]

To date, knowledge about LRRK2 -mutation status does not alter therapeutic management, since targeted, neuroprotective therapies are still at an experimental stage. Clinical implications are, therefore, limited to the identification of mutation carriers for research studies. Thus, routine genetic testing for LRRK2 mutations remains a controversial topic; this is particularly true when testing of asymptomatic relatives of PD patients is considered.

Within the context of a research study, information on the ethnic background of a proband allows testing for mutations that are most prevalent in that ethnic population, thereby avoiding excessive and costly screening. In individuals of Caucasian, Ashkenazi Jewish, or North African Berber ancestry, testing for the G2019S mutation would be recommended, while patients of Spanish or Hispanic descent should also be evaluated for R1441G mutations. Given the limited knowledge on clinical consequences of the common risk-modifying variants G2385R and R1628P, genetic screening for these mutations should not be encouraged.

PD associated with LRRK2 mutations is an autosomal-dominant disease. It therefore follows that each child of an LRRK2 mutation carrier has a 50% chance of inheriting the mutation. However, due to incomplete penetrance, only a fraction of these individuals will develop disease, and age is the main influencing disease penetrance.

Elevated ratio of phosphorylated Ser-1292 LRRK2 to total LRRK2 in urine exosomes predicted LRRK2 mutation status and PD risk among LRRK2 mutation carriers in one study. The urinary exosomes were collected from 2 independent cohorts. The first cohort included 14 men (LRRK2+/PD+, N = 7; LRRK2-/PD+, N = 4; LRRK2-/PD-, N = 3). The second cohort included 62 men (LRRK2-/PD-, N = 16; LRRK2+/PD-, N = 16; LRRK2+/PD+, N = 14; LRRK2-/PD+, N = 16). [27]   

Current therapy for PD focuses on drugs that manage the symptoms but do not affect the disease progression. Research is being conducted that involves inhibitors of kinases (enzymes that regulate cellular signaling) and how they may affect the neurologic pathways associated with PD. Unfortunately, at this time, the repeated failure of neuroprotective drugs in animal models suggests that there are likely multiple processes involved. A coalescing molecular pathway for the disease still remains elusive. [28, 29, 30, 31]

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Aasly JO, Shi M, Sossi V, et al. Cerebrospinal amyloid ß and tau in LRRK2 mutation carriers. Neurology. 2012 Jan 3. 78(1):55-61. [Medline].

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Henry AG, Aghamohammadzadeh S, Samaroo H, Chen Y, Mou K, Needle E, et al. Pathogenic LRRK2 mutations, through increased kinase activity, produce enlarged lysosomes with reduced degradative capacity and increase ATP13A2 expression. Hum Mol Genet. 2015 Nov 1. 24 (21):6013-28. [Medline].

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Andrew Singleton, PhD Senior Investigator with Tenure, Chief of the Molecular Genetics Section and Chief of the Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health

Disclosure: Nothing to disclose.

Sonja Scholz, MD, PhD Resident Physician, Department of Neurology, Johns Hopkins University School of Medicine

Sonja Scholz, MD, PhD is a member of the following medical societies: American Academy of Neurology, International Parkinson and Movement Disorder Society

Disclosure: Nothing to disclose.

Keith K Vaux, MD Professor of Medicine, Clinical Chief and Division Director, Division of Medical Genetics, Department of Medicine, University of California, San Diego, School of Medicine; Director, Rare Disease Program, Rady Children’s Hospital San Diego and UC San Diego

Keith K Vaux, MD is a member of the following medical societies: American Academy of Pediatrics, Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Parkinson Disease and LRRK2

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