Parkinson Disease and LRRK2 

Updated: Dec 29, 2020
  • Author: Andrew Singleton, PhD; Chief Editor: Keith K Vaux, MD  more...
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Association of LRRK2 with Parkinson Disease

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]  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 some LRRK2 mutations (G2019S, G2385R, N1437H, R1441C, R1441G, R1441H, R1628P, I2020T, and Y1699C) are unequivocally linked to disease based on disease segregation in large families and functional studies. [4, 5, 6, 7, 8]  G2019S and I2020T mutations are located in the kinase domain; N1437H and R1441C/G/H in the ROC domain; and Y1699C in the COR domain. The aberrant kinase activity of pathogenic LRRK2 mutations apparently induce neurodegeneration by disturbing intracellular processes such as protein translation, endolysosomal pathway, autophagy, synaptic functions, and cytoskeleton dynamics. [9, 10, 11]

LRRK2 mutations have been identified as being associated with both the familial and idopathic forms of PD; however, the role of wild-type LRRK2 in the etiology of idopathic PD is not fully understood. [12]

LRRK2-associated Parkinson disease is characterized have the same features as those of  idiopathic PD, including initial motor features of slowly progressive asymmetric tremor at rest and/or bradykinesia, cogwheel muscle rigidity, postural instability, and gait abnormalities that may include festination and freezing. Onset of LRRK2-associated PD is generally after 50 years of age. [9, 13]

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. [14]

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. [15]

Epidemiology

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, [16, 17] thus accounting 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. [18, 19, 20, 21, 22] Of note, genetic data point toward a single founder for the vast majority of the G2019S PD cases. [23]

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. [24]

Genetic risk modifiers

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. [25, 26]

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. [27]

Penetrance

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. [28, 29, 30]

Disease presentation

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, 23, 31, 32] :

  • 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, 33]

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Clinical Implications and Genetic Testing

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 risk factor influencing disease penetrance.

Elevated ratio of phosphorylated Ser-1292 LRRK2 to total LRRK2 in urine exosomes predicted LRRK2 mutation status and PD risk in LRRK2 mutation carriers in a study by Fraser et al. 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). [34]    

Sensitive quantitative markers of LRRK2 activation are still at the very early stages of development. Several measures of LRRK2 activity have been proposed for use in longitudinal studies of disease progression, such as levels of LRRK2, phosphorylation of LRRK2, in vitro kinase activity, and phosphorylation of downstream substrates. [35]

Substantial effort has been devoted to the development and testing of potent and selective small molecule inhibitors of LRRK2. [36] 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. [37, 38, 39, 40]

Two LRRK2 kinase inhibitors, DNL201 and DNL151, are in clinical development. A randomized, placebo-controlled phase Ib clinical trial of DNL201 in patients with mild to moderate PD with and without LRRK2 mutations will assess safety and obtain data about biomarkers of safety and target engagement. Global phase II trials are being planned. [41, 42]

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