Parkin Disease Research Articles

Impulsive and compulsive parkin disease

In this issue of Neurology ®, Morgante et al.1 present a nice genotype–phenotype study of parkin -associated Parkinson disease (PD). PD is a progressive neurodegenerative disorder that affects 4.1 to 4.6 million people worldwide2 and results in motor dysfunction and nonmotor symptoms including psychiatric problems. Impulse control disorder (ICD) is one such psychiatric problem that may present in PD. These impulsive behaviors are diverse and include excessive shopping, hypersexuality, binge-eating behavior, and pathologic gambling.3,4 The incidence of ICDs is higher in patients with PD who have been treated with long-term dopaminergic replacement therapy including dopamine agonists, levodopa, and amantadine. Increasing evidence suggests that higher levodopa equivalent daily dose, male sex, younger age at PD onset, history of alcoholism, history of smoking, family history of gambling problems, and novelty-seeking personality are risk factors of ICD.4 In addition, imaging studies propose potential neural networks that may underlie impulsivity and ICDs in PD.5 The prevalence of ICD in treated PD can be up to 35%.6 However, in routine clinical practice, ICDs are often diagnosed late or remain undiagnosed and untreated. The authors thank Drs. Bill Dauer, Conor Fearon, John Krakauer, Diana Olszewska, and Eavan McGovern for their very helpful discussion and advice in drafting this editorial.

Quantitative gait analysis in parkin disease: Possible role of dystonia.

Parkin disease (PARK2, OMIM 602544) is an autosomal-recessive early-onset parkinsonism characterized by an early occurrence of lower limb dystonia. The aim of this study was to analyze spatiotemporal, kinematic, and kinetic gait parameters in patients with parkin disease in the OFF and ON conditions compared to healthy age-matched controls. Fifteen patients with parkin disease and 15 healthy age-matched controls were studied in a gait analysis laboratory with an integrated optoelectronic system. Spatiotemporal, kinematic, and kinetic gait parameters at a self-selected speed were recorded in the OFF and ON conditions. A jerk index was computed to quantify the possible reduction of smoothness of joint movements. Compared to controls, parkin patients had, either in the OFF or in the ON conditions, significant reduction of walking velocity, increased step width, and decreased percentage of double support. Kinematic analysis in both conditions showed: increased ankle dorsiflexion and knee flexion at the initial contact; maximal flexion and increased range of motion in mid stance; increased hip flexion and max extension in stance at pelvis; and increased mean tilt antiversion. Kinetics showed increased hip and knee power generation in stance in either condition. The jerk index was increased at all joints both in OFF and ON. There were no correlations between individual gait parameters and clinical ratings. Parkin patients have an abnormal gait pattern that does not vary between the OFF and the ON conditions. Variations recorded with instrumented analysis are more evident for kinematic than kinetic parameters at lower limbs. Severity of dystonia does not correlate with any individual kinematic parameter. © 2016 International Parkinson and Movement Disorder Society.

Central Parkin: The evolving role of Parkin in the heart

Parkin is familiar to many because of its link to Parkinson's disease, and to others because of its well-characterized role as a central factor mediating selective mitophagy of damaged mitochondria for mitochondrial quality control. The genetic connection between Parkin and Parkinson's disease derives from clinical gene-association studies, whereas our mechanistic understanding of Parkin functioning in mitophagy is based almost entirely on work performed in cultured cells. Surprisingly, experimental evidence linking the disease and the presumed mechanism derives almost entirely from fruit flies; germline Parkin deficient mice do not develop Parkinson's disease phenotypes. Moreover, genetic manipulation of Parkin signaling in mouse hearts does not support a central role for Parkin in homeostatic mitochondrial quality control in this mitochondria-rich and -dependent organ. Here, I provide an overview of data suggesting that (in mouse hearts at least) Parkin functions more as a stress-induced and developmentally-programmed facilitator of cardiomyocyte mitochondrial turnover. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2–6, 2016.

Linking a compound-heterozygous Parkin mutant (Q311R and A371T) to Parkinson's disease by using proteomic and molecular approaches

Parkin is an E3-protein ubiquitin ligase, which plays an important role as a scavenger in cell metabolism. Since the discovery of the link between Parkin and Parkinson's disease, Parkin was placed in the center of Parkinson's disease research. Previously, we isolated a mutant form of the Parkin protein (Q311R and A371T) from a Parkinson's disease patient. In this study, we aimed at characterizing this mutant Parkin protein by using biochemical and proteomic approaches. We used neuroblastoma cells (SH-SY5Y) as our model and created two inducible cell lines that expressed the wild type and the mutant Parkin proteins. We first investigated the effect of expressing both the wild type and the mutant Parkin proteins on the overall proteome by using 2D-DIGE approach. The experiments yielded the identification of 22 differentially regulated proteins, of which 13 were regulated in the mutant Parkin expressing cells. Classification of the identified proteins based on biological process and molecular function revealed that the majority of the regulated proteins belonged to protein folding and energy metabolism. Ingenuity Pathway Analysis predicted the presence of a link between the regulated proteins of the mutant Parkin expressing cells and Parkinson's disease. We also performed biochemical characterization studies on the wild type and the mutant Parkin proteins to make sense out of the differences observed at the proteome level. Both proteins displayed biological activity, had similar stabilities and localized similarly to the cytoplasm and the nucleus in SH-SY5Y cells. The mutant protein, however, was cut by a protease and subjected to a post-translational modification. The observed differences at the proteome level might be due to the differences in processing of the mutant Parkin protein. Overall, we were able to create a possible link between a pair of Parkin mutations to its pertinent disease by using 2D-DIGE in combination with biochemical and molecular approaches.

Re-defining Parkinson disease

Analyzing non-motor symptoms in Parkinson’s disease (PD) leads to critically re-define and update the disorder itself. The present Editorial encompasses epidemiological and clinical studies on PD patients joined with experimental findings to provide a novel definition of PD based on clinical, neuroanatomical and neurobiological findings. In fact, the plethora of symptoms described in PD patients are due to specific anatomical alterations which cluster in specific disease phenotypes. These PDs differ for disease onset and progression, disease severity and specific cluster of non-motor disturbances. Despite the variety of PD phenotypes, it is now well established that in almost all PD subgroups (except those autosomic recessive selective disorders exemplified by Parkin disease) a core anatomical defnition exists recruiting a variety of brainstem monoamine nuclei. Such a variety of PD pathologies can be defined as monoamine brainstem disorder (MBD).

PARKIN DISEASE–A CLINICOPATHOLOGICAL ENTITY?

IntroductionMutations in the gene encoding parkin (PARK2) are the commonest cause of autosomal recessive juvenile and young onset parkinsonism. The few available detailed neuropathological reports suggest that homozygous and compound...

Parkin disease and the Lewy body conundrum.

A clear pathologic hallmark like that identified in sporadic Parkinson’s disease (PD) is lacking in many of the monogenic causes of PD. In leucine-rich repeat kinase 2 (LRRK2) mutations (PARK8), alpha-synuclein pathology in the form of Lewy bodies (LBs) is frequently, but not consistently, observed. Other pathologies reported in LRRK2 cases include tau inclusions of the Alzheimer, progressive supranuclear palsy, and frontotemporal lobar degeneration types, and TAR DNA-binding protein 43 (TDP-43) inclusions. 1 There has been only a single report of a compound heterozygous, phosphatase and tensin homolog (PTEN)-induced, putative kinase 1 (PINK1; PARK6) patient coming to autopsy. 2 That patient presented with asymmetrical rigidity at age 31 years and had a good motor response to dopaminergic therapy, but died at age 39 years. Pathologic study revealed nigral neuronal loss and gliosis, with a few LBs and Lewy neurites identified in the substantia nigra (SN), nucleus basalis of Meynert (NBM), and reticular formation of the brainstem, but not in the locus coeruleus (LC),

Quantitative gait analysis in parkin disease

Quantitative gait analysis in parkin disease

Re-defining Parkinson's disease.

Analyzing non-motor symptoms in Parkinson's disease (PD) leads to critically re-define and update the disorder itself. The present Editorial encompasses epidemiological and clinical studies on PD patients joined with experimental findings to provide a novel definition of PD based on clinical, neuroanatomical and neurobiological findings.In fact, the plethora of symptoms described in PD patients are due to specific anatomical alterations which cluster in specific disease phenotypes. These PDs differ for disease onset and progression, disease severity and specific cluster of non-motor disturbances. Despite the variety of PD phenotypes, it is now well established that in almost all PD subgroups (except those autosomic recessive selective disorders exemplified by Parkin disease) a core anatomical defniition exists recruiting a variety of brainstem monoamine nuclei. Such a variety of PD pathologies can be defined as monoamine brainstem disorder (MBD).

Parkin and Parkinson Disease

Featured Article: Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 2000;25:302–5.5 Since the 1970s, Japanese neurologists have described patients with autosomal recessive forms of familial Parkinson disease (PD),6 which have been termed “autosomal recessive juvenile parkinsonism” and “early-onset parkinsonism with diurnal fluctuation,” both of which have become known as “PARK2” (1). We attempted to identify the gene responsible for autosomal recessive familial PD. In 1997, we identified, along with our collaborators, an autosomal recessive familial PD gene between D6S437 and D6S264 (2), and in 1998 we found that mutations in that gene were linked to autosomal recessive familial PD. We designated the gene, formerly known as parkin , as PARK2 7 \[parkinson protein 2, E3 ubiquitin protein ligase (parkin)\] (3). Parkin is a 465-amino-acid protein containing an N-terminal …

Lack of association between p.Ser167Asn variant of Parkin and Parkinson's disease: A meta‐analysis of 15 studies involving 2,280 cases and 2,459 controls

Previous clinical trials have evaluated the association between Parkin p.Ser167Asn (c.601G>A) variant and Parkinson's disease (PD) risk. However, the results remain conflicting rather than conclusive. Therefore, we performed this meta-analysis to assess whether pooled results show the association. We performed structured literature searches for studies addressing the association between the Parkin p.Ser167Asn variant and PD risk. We conducted analyses of study characteristics, heterogeneity, and funnel plot asymmetry in analyses analogous to additive, dominant, recessive, and general genetic models with the odds ratio (OR) as the measure of association. When 15 eligible studies (n = 4,739 subjects) were pooled into the meta-analysis, there was no evidence for significant association in additive genetic model between Parkin p. Ser167Asn variant and PD risk (OR = 1.02, 95% confidence interval (CI) = 0.83-1.25; P = 0.866). The OR for the dominant model was 1.06 (95% CI = 0.80-1.41) while the OR for the recessive model was 0.90 (95% CI = 0.71-1.14). The OR for the heterozygous was 1.07 (95% CI = 0.80-1.43) while the OR for the homozygotes was 1.19 (95% CI = 0.81-1.74). In the subgroup analysis by ethnicity, no significant association was found in any genetic model. Begg's funnel plot and Egger's test provided visual and statistical evidences for funnel plot symmetry, suggesting no presence of publication bias. In summary, the meta-analysis strongly suggests that Parkin p. Ser167Asn variant is not associated with PD risk.

Novel Regulation of Parkin Function through c-Abl-Mediated Tyrosine Phosphorylation: Implications for Parkinson's Disease

Mutations in parkin, an E3 ubiquitin ligase, are the most common cause of autosomal-recessive Parkinson's disease (PD). Here, we show that the stress-signaling non-receptor tyrosine kinase c-Abl links parkin to sporadic forms of PD via tyrosine phosphorylation. Under oxidative and dopaminergic stress, c-Abl was activated in cultured neuronal cells and in striatum of adult C57BL/6 mice. Activated c-Abl was found in the striatum of PD patients. Concomitantly, parkin was tyrosine-phosphorylated, causing loss of its ubiquitin ligase and cytoprotective activities, and the accumulation of parkin substrates, AIMP2 (aminoacyl tRNA synthetase complex-interacting multifunctional protein 2) (p38/JTV-1) and FBP-1.STI-571, a selective c-Abl inhibitor, prevented tyrosine phosphorylation of parkin and restored its E3 ligase activity and cytoprotective function both in vitro and in vivo. Our results suggest that tyrosine phosphorylation of parkin by c-Abl is a major post-translational modification that leads to loss of parkin function and disease progression in sporadic PD. Moreover, inhibition of c-Abl offers new therapeutic opportunities for blocking PD progression.

Parkin and Parkinson's disease: Differentiated by non-dopaminergic dysfunction?

Parkin and Parkinson's disease: Differentiated by non-dopaminergic dysfunction?

In vivo assessment of brain monoamine systems in parkin gene carriers: A PET study

PET studies in parkin-linked parkinsonism have generally been performed to assess striatal dopaminergic dysfunction and very little is known about the involvement of other monoaminergic structures in these patients. Measurements of (18)F-dopa uptake into serotonergic and noradrenergic structures provide an indication of the functional integrity of these nerve terminals. We used (18)F-dopa PET to assess changes in brain monoaminergic function associated with parkin mutations. Twelve patients with parkin-linked parkinsonism and 12 asymptomatic parkin heterozygotes were included in the study. Eleven healthy controls, 12 patients with idiopathic Parkinson's disease (IPD), and four patients with PINK1 mutations were also investigated for comparison. parkin patients and IPD patients were matched for striatal dopaminergic dysfunction, as measured by (18)F-dopa uptake. Compared to controls, parkin patients showed significant (18)F-dopa reductions in the caudate, putamen, ventral striatum, locus coeruleus, midbrain raphe, and pallidum. The same structures showed reduced uptake in IPD patients, who additionally had significant reductions in hypothalamus, ventral anterior thalamus, and pineal gland. Direct comparison of parkin with IPD patients showed that hypothalamus was targeted in IPD and midbrain raphe in parkin disease. Patients with PINK1 mutation and several parkin heterozygotes also showed monoaminergic dysfunction. These findings suggest that parkin patients and IPD patients with similar striatal dysfunction have different patterns of monoaminergic involvement, with more widespread dysfunction in IPD.

Health Related Quality of Life in Patients With Spina Bifida: A Prospective Assessment Before and After Lower Urinary Tract Reconstruction

In a previous retrospective cohort study we challenged the assumption that lower urinary tract reconstruction improves health related quality of life in spina bifida cases. We readdressed this issue prospectively in a new series of patients. A total of 31 consecutive incontinent patients with spina bifida undergoing reconstruction with a continent stoma with or without augmentation, with or without bladder neck reconstruction and with or without cecostomy were assessed preoperatively and 6 months postoperatively with the Parkin disease specific health related quality of life score. The instrument stratifies patients by ages 12 years or younger and 13 years or older. An additional 4-item questionnaire was used to score bladder and bowel continence. There was no significant change in health related quality of life following surgery in either age group. The median score changed from 167 to 174 in patients 12 years old or younger (p = 0.74) and from 199 to 193 in patients 13 years old or older (p = 0.42) despite a significant improvement in scores on all continence questions (p <0.05). In patients 12 years old or younger there was significant improvement in 3 items in the domains of independence and emotional expression (p <0.05). In adolescents 4 items changed significantly, and all were related to the independence and emotional domains (p <0.05). Despite improvement in some question items we did not note an improvement in overall quality of life following reconstruction. Correcting only 1 system in a profound multisystem disability may be insufficient to improve health related quality of life or perhaps only caregiver quality of life is improved. The impact of lower urinary tract reconstruction on quality of life in patients with spina bifida requires further assessment before improvements are assumed.

Parkin Deficiency Delays Motor Decline and Disease Manifestation in a Mouse Model of Synucleinopathy

In synucleinopathies, including Parkinson's disease, partially ubiquitylated α-synuclein species phosphorylated on serine 129 (PS129-α-synuclein) accumulate abnormally. Parkin, an ubiquitin-protein ligase that is dysfunctional in autosomal recessive parkinsonism, protects against α-synuclein-mediated toxicity in various models.We analyzed the effects of Parkin deficiency in a mouse model of synucleinopathy to explore the possibility that Parkin and α-synuclein act in the same biochemical pathway. Whether or not Parkin was present, these mice developed an age-dependent neurodegenerative disorder preceded by a progressive decline in performance in tasks predictive of sensorimotor dysfunction. The symptoms were accompanied by the deposition of PS129-α-synuclein but not PS87-α-synuclein in neuronal cell bodies and neuritic processes throughout the brainstem and the spinal cord; activation of caspase 9 was observed in 5% of the PS129-α-synuclein-positive neurons. As in Lewy bodies, ubiquitin-immunoreactivity, albeit less abundant, was invariably co-localized with PS129-α-synuclein. During late disease stages, the disease-specific neuropathological features revealed by ubiquitin- and PS129-α-synuclein-specific antibodies were similar in mice with or without Parkin. However, the proportion of PS129-α-synuclein-immunoreactive neuronal cell bodies and neurites co-stained for ubiquitin was lower in the absence than in the presence of Parkin, suggesting less advanced synucleinopathy. Moreover, sensorimotor impairment and manifestation of the neurodegenerative phenotype due to overproduction of human α-synuclein were significantly delayed in Parkin-deficient mice.These findings raise the possibility that effective compensatory mechanisms modulate the phenotypic expression of disease in parkin-related parkinsonism.

Mitochondrial Pathology in Muscle of a Patient with a Novel Parkin Mutation

Mutations of the parkin gene on chromosome 6 cause early-onset parkinsonism. Myopathy has not been reported to be a feature of this condition. Here we report the muscle biopsy findings of a 53-year-old man with a novel parkin gene mutation (IVS-9-1 deletion). His symptoms were characterized by typical early-onset, dopa-responsive, and slowly progressive parkinsonism. Parkin gene analysis revealed a homozygous IVS-9-1 deletion in the proband and his sibling. The unusual feature was hypertrophy of bilateral thigh muscles in the proband. Muscle biopsy from the biceps brachii muscle showed abundant cytochrome oxidase (COX) (−) fibers. This is the first report on the coexistence of a myopathy with COX deficiency with parkin disease and may shed light on the function of parkin in muscle.

Normal cardiovascular reflex testing in patients with parkin disease

The objective of this study was to investigate cardiovascular autonomic function in patients with parkin disease. Ten patients with a genetically confirmed diagnosis were compared to 11 healthy controls. Symptoms related to autonomic dysfunction were collected by structured interviews. Cardiovascular autonomic reflex function was evaluated using a standard battery of eight tests. Autonomic tests included the study of sympathetic function through the analysis of blood pressure responses to head-up tilt, standing, isometric hand grip, cold pressor, mental arithmetic, Valsalva maneuver (Valsalva overshoot), and the study of parasympathetic function through the analysis of heart rate responses to deep breathing, hyperventilation, and Valsalva ratio. Seven out of 10 patients reported symptoms involving different aspects of autonomic function, while 5 out of 11 controls reported symptoms related exclusively to orthostatic dizziness and constipation. Symptoms related to bladder dysfunction were the most frequent autonomic abnormality occurring in six patients, followed by orthostatic dizziness and dry mouth (in four patients each). Constipation occurred in three patients, sialorrhea in two, and erectile dysfunction, dry eye, and warm intolerance in one each. Cardiovascular reflex testing revealed no difference between patients and controls in quantitative assessment of both sympathetic and parasympathetic functions, except for diastolic blood pressure after isometric hand grip that did not increase normally in parkin patients compared to controls (P = 0.007). These data show that cardiovascular dysautonomia is not associated to the parkin phenotype, whereas urinary complaints are more frequently reported by parkin patients than by controls. Urinary dysautonomia warrants further investigation in patients with parkin disease.

Neurophysiological evidence of corticospinal tract abnormality in patients with Parkin mutations

Mutations in the parkin gene (PARK2) are the most frequent cause of autosomal recessive early-onset Parkinson disease. We performed a transcranial magnetic stimulation study in four patients with parkin mutations. Two patients had a prolonged central motor conduction time at both upper and lower limb, one only at the arm and one only at the leg. The MEP threshold was increased in one patient for the arm and in two for the leg. The MEP amplitude was reduced in one and central silent period shortened in two. The findings demonstrate corticospinal dysfunction in these patients and suggest that the extent of central nervous system involvement in parkin disease may be wider that hitherto supposed.

NITRITE AND MALONDIALDEHYDE CONTENT IN CEREBROSPINAL FLUID OF PATIENTS WITH PARKINSON’S DISEASE

Evidence from clinical and experimental studies supports the hypothesis of free radical–mediated damage of dopaminergic neurons in the pathology of Parkin's disease (PD). The present study was undertaken to evaluate the role of nitric oxide and oxidative stress in PD. Estimation of the stable metabolites of nitric oxide (NO, nitrite, nitrate) and malondialdehyde (MDA), an acceptable marker of lipid peroxidation, can provide indirect evidence of involvement of free radicals. Nitrite and malondialdehyde (MDA) levels were estimated in the lumbar cerebrospinal fluid (CSF) of 20 controls and 21 patients with PD. Nitrite and MDA content was not significantly altered in the CSF of PD patients as compared to the controls. Nitrite and MDA levels in CSF of PD patients exhibited no correlation with age, duration of disease, and severity of illness (measured by the Unified Parkinson's Disease Rating Score). There was no correlation between the CSF nitrite and MDA level. Findings of the present study do not provide evidence for the involvement of nitric oxide and oxidative stress in PD.