Hatano et al. (2004) reported 8 unrelated families with autosomal recessive PD from various regions in Asia that showed linkage to the PARK6 locus. Five families were consanguineous. Age at onset ranged from 18 to 56 years, although ... Hatano et al. (2004) reported 8 unrelated families with autosomal recessive PD from various regions in Asia that showed linkage to the PARK6 locus. Five families were consanguineous. Age at onset ranged from 18 to 56 years, although most had onset in the third or fourth decades. The main clinical features included rigidity, bradykinesia, asymmetric onset, postural instability, and favorable response to levodopa. Other variable features included resting tremor, frozen gait, sleep benefit, dystonia at onset (in 2 patients), hyperreflexia, and levodopa-induced dyskinesias. Progression was generally slow. Bonifati et al. (2005) identified homozygous mutations in the PINK1 gene in 4 of 90 sporadic Italian patients with early-onset parkinsonism. Age at onset ranged from 28 to 35 years, and the disorder was characterized by tremor, bradykinesia, rigidity, postural instability, response to L-dopa, and L-dopa-induced dyskinesias. Two patients had asymmetric onset, 3 had dystonia at onset, and 2 reported benefit from sleep. Another 4 sporadic patients had heterozygous mutations in the PINK1 gene. Clinical features in this group were similar to those with homozygous mutations, except for a later age at onset (34 to 45 years). Bonifati et al. (2005) concluded that heterozygous PINK1 mutations may predispose some patients to disease development. Albanese et al. (2005) described in detail the phenotype of a patient with PARK6 confirmed by genetic analysis. At age 39 years, he developed gait impairment due to akinesia of the right leg, followed by motor impairment of the upper right limb and favorable response to levodopa treatment. Fifteen years later, he had facial hypomimia, mild akinesia in the upper limbs, and mild periodic dystonia of the right foot. Sleep benefit, dystonia at onset, hyperreflexia, levodopa-induced dyskinesias, and cognitive impairment were absent. Other studies showed mild dysautonomia, striatal dopaminergic denervation, and normal skeletal muscle mitochondrial function. Albanese et al. (2005) concluded that the clinical phenotype in this patient was indistinguishable from idiopathic PD. In a review of 21 patients with PINK1-related parkinsonism reported in the literature, Albanese et al. (2005) found that most patients (95 to 100%) had slow disease progression, good response to levodopa, bradykinesia, and rigidity. Also common were levodopa-induced dyskinesias (84%), resting tremor (80%), asymmetry at onset (74%), postural instability (63%), on/off phenomenon (60%), and gait impairment (55%). Other less common features included urinary urgency (44%), hyperreflexia (33%), sleep benefit (31%), psychiatric disturbances (25%), orthostatic hypotension (22%), dystonia at onset (16%), and dementia (5%). Thus, although most patients with PARK6 have features similar to those of idiopathic PD, a subset demonstrate features similar to those of PARK2 (600116). - Neuropathologic Findings Samaranch et al. (2010) reported the neuropathologic findings of a Spanish patient from a large family with autosomal recessive PARK6. He first developed pain and rigidity in his left shoulder and arm at age 31 years. The disorder was progressive, and he showed gait impairment and postural instability that was responsive to dopamine treatment. He also had comorbid psychiatric disturbances, including cocaine addiction before the onset of parkinsonism, anxiety, increasingly strange behavior, and psychosis. He died at age 39 of nonnatural causes. There was neuronal loss in the substantia nigra with astrocytic gliosis and moderate microgliosis. A few remaining neurons showed Lewy bodies. There was no apparent cell loss or Lewy bodies in the locus ceruleus or amygdala. Lewy bodies were also found in some regions of the brainstem. The findings indicated that PINK1 mutations cause an alpha-synucleinopathy (SNCA; 163890). Of note, heterozygous mutation carriers in the family were not affected.
Valente et al. (2004) identified 2 different homozygous mutations affecting the PINK1 kinase domain in 3 consanguineous PARK6 families. Cell culture studies suggested that PINK1 is mitochondrially located and may exert a protective effect on the cell that ... Valente et al. (2004) identified 2 different homozygous mutations affecting the PINK1 kinase domain in 3 consanguineous PARK6 families. Cell culture studies suggested that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress. Valente et al. (2004) concluded that their data provided a direct molecular link between mitochondria and the pathogenesis of Parkinson disease. In 6 unrelated families (3 Japanese, 1 Israeli, 1 Filipino, and 1 Taiwanese) with PARK6, Hatano et al. (2004) identified 6 pathogenic mutations in the PINK1 gene (see, e.g., 608309.0003-608309.0005). The authors suggested that PINK1 may be the second most common causative gene next to parkin in early-onset autosomal recessive Parkinson disease. These families had also been reported by Hatano et al. (2004). Valente et al. (2004) found that among 90 patients with sporadic early-onset parkinsonism, 1 patient had a homozygous mutation in the PINK1 gene and a second was compound heterozygous for mutations in PINK1. Five of 90 patients and 2 of 200 healthy controls had a heterozygous PINK1 mutation; 1 of the patients and 1 control shared the same mutation. The 5 patients with a heterozygous mutation had a typical parkinsonian phenotype with a mean age at onset of 44 years. Three patients had mild mood disturbances. Valente et al. (2004) suggested that heterozygous PINK1 mutations may produce subclinical dopaminergic dysfunction and represent a risk factor for the development of parkinson disease. In 3 of 65 unrelated Italian patients with early-onset parkinsonism, Klein et al. (2005) identified 2 different mutations in the PINK1 gene (608309.0007 and 608309.0008). One patient was homozygous, and 2 patients were heterozygous. Chishti et al. (2006) identified homozygosity for a mutation in the PINK1 gene (608309.0010) in affected members of a large consanguineous PARK6 family from Saudi Arabia, and Leutenegger et al., 2006 identified homozygosity for a PINK1 mutation (608309.0011) in affected members of a large consanguineous PARK6 family from northern Sudan. Heterozygous individuals in these families did not have signs of parkinsonism. Hedrich et al. (2006) identified a homozygous mutation (Q456X; 608309.0012) in the PINK1 gene in 4 affected members of a large German family with early-onset parkinsonism. Six heterozygous offspring of the homozygous patients were found to have subtle signs of disease, and 5 heterozygous offspring were considered to be unaffected. The 6 affected heterozygous offspring were not aware of their signs, but clinical examination showed unilaterally reduced or absent arm swing and rigidity. Hedrich et al. (2006) concluded that heterozygous PINK1 mutations confer susceptibility to the development of PD. Of clinical note, parkinsonian signs were more marked on the dominant right-hand side in all mutation carriers, and 10 of 15 mutation carriers had psychiatric disturbances. Abou-Sleiman et al. (2006) identified heterozygous mutations in the PINK1 gene (see, e.g., 608309.0013) in 9 (1.2%) of 768 patients with sporadic PD. Heterozygous mutations were identified in 0.39% of a larger control group without PD, suggesting that heterozygous PINK1 mutations are a risk factor for PD. The mean age of symptom onset in the patients was 54 years, and the disorder showed very slow progression. Choi et al. (2008) identified mutations in the PINK1 gene (see, e.g., 608309.0008) in 4 of 72 unrelated Korean patients with onset of PD before age 50. Three patients were heterozygous, and 1 was compound heterozygous for the mutation(s). Kumazawa et al. (2008) identified mutations in the PINK1 gene in 10 (2.5%) of 391 unrelated parkin-negative PD patients from 13 countries. Eight of the 10 patients with mutations were from Japan. The frequency of homozygous mutations was 4.26% (2 of 47) in families with autosomal recessive PD and 0.53% (1 of 190) in patients with sporadic PD. The frequency of heterozygous mutations was 1.89% (2 of 106) in families with potential autosomal dominant PD and 1.05% (2 of 190) in patients with sporadic PD. The mean age at onset in patients with single heterozygous mutations was 53.6 years, compared to 34.0 years in patients with homozygous mutations. Ishihara-Paul et al. (2008) identified 4 different homozygous mutations in the PINK1 gene (see, e.g., Q456X; 608309.0012), including 3 novel mutations, in 14 (15%) of 92 Tunisian families with early-onset Parkinson disease. Six (2.5%) of 240 patients with no family history of PD. were also found to carry homozygous mutations. There was no evidence that heterozygous PINK1 mutations contributed to development of PD. - Modifier Genes Piccoli et al. (2008) reported a family with early-onset PARK6 associated with a mutation (W437X; 608309.0002) in the PINK1 gene. The proband, who had very early onset at age 22 years, was homozygous for the W437X mutation, whereas both his parents were heterozygous. The father was unaffected at age 79, and the mother developed Parkinson disease at age 53. Biochemical studies of the proband's fibroblasts showed mitochondrial dysfunction, with decreased amounts of cytochrome c oxidase, impaired complex I activity, and increased hydrogen peroxide generation. Further analysis identified 2 mutations in mitochondrial genes: MTND5 (516005.0010) and MTND6 (516006.0008). Both the proband and his mother were homoplasmic for both mitochondrial mutations. Piccoli et al. (2008) concluded that the presence of the mitochondrial mutations in combination with the PINK1 mutation may have accelerated onset of the disease. - Parkinson Disease, Digenic, PINK1/DJ1 In 2 Chinese sibs with early-onset Parkinson disease, Tang et al. (2006) identified compound heterozygosity for a missense mutation (608309.0014) in the PINK1 gene and a missense mutation (602533.0007) in the DJ1 gene. The DJ1 and PINK1 mutations were not observed in 240 and 568 control chromosomes, respectively, and both were located in highly conserved residues. The findings were consistent with digenic inheritance of Parkinson disease. A 42-year-old unaffected family member also carried both mutations, suggesting incomplete penetrance. Coimmunoprecipitation studies showed that both wildtype and mutant PINK1 interacted with both wildtype and mutant DJ1. Expression of wildtype DJ1 increased steady-state levels of both mutant and wildtype PINK1, but mutant DJ1 decreased steady-state levels of both mutant and wildtype PINK1, suggesting that wildtype DJ1 can enhance PINK1 stability. Human neuroblastoma cells expressing either mutant PINK1 or DJ1 showed reduced viability following oxidative challenge with MPP compared to control cells, indicating that both proteins protect against cell stress. Coexpression of both wildtype proteins resulted in a synergistic increase in cell viability against MPP-induced stress. In addition, coexpression of both mutant proteins significantly increased susceptibility of cells to death, compared to either mutant alone. These findings indicated that DJ1 and PINK1 function collaboratively.
To date no guidelines regarding diagnostic criteria or algorithms specifically addressed to PINK1 Parkinson disease have been developed. ...
DiagnosisTo date no guidelines regarding diagnostic criteria or algorithms specifically addressed to PINK1 Parkinson disease have been developed. Clinical DiagnosisThe PINK1 type of young-onset Parkinson disease is often clinically indistinguishable from idiopathic Parkinson disease. Rigidity, bradykinesia, and rest tremor are variably combined in both disorders.The following findings suggest PINK1 type of young-onset Parkinson disease: Early onset (age <40 years) or juvenile onset (age <20 years). Most affected individuals appear to have onset before age 40 years. Lower-limb dystonia can be a presenting sign or occurs during disease progression. Marked and sustained response to oral administration of levodopa, frequently associated with levodopa-induced fluctuations and dyskinesias (abnormal involuntary movements) [Nishioka et al 2009]. Sleep benefit is observed in some [Li et al 2005]. Slow disease progression A family history consistent with autosomal recessive inheritance TestingNo clinical investigations unambiguously distinguish individuals with the PINK1 type of young-onset Parkinson disease from those with idiopathic Parkinson disease. Molecular Genetic Testing Gene. PINK1 is the only gene in which mutations are known to cause PINK1 type of young-onset Parkinson [Valente et al 2004b]. Clinical testing Table 1. Summary of Molecular Genetic Testing Used in PINK1 Type of Young-Onset Parkinson DiseaseView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityPINK1Sequence analysisSequence variants 2>90%ClinicalDeletion / duplication analysis 3Exonic and whole-gene deletions<10%Targeted mutation analysisp.Gly309AspUnknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. Interpretation of test resultsFor issues to consider in interpretation of sequence analysis results, click here. The diagnosis of the PINK1 type of young-onset Parkinson disease can be confirmed only when disease-causing mutations are identified on both PINK1 alleles (i.e., the individual is homozygous for the same disease-causing allele or a compound-heterozygote for two different disease-causing alleles). The finding of a single disease-causing mutation is only suggestive (i.e., not diagnostic) of the PINK1 type of young-onset Parkinson disease. While the affected individual may be a heterozygote, the cause of parkinsonism may be unrelated to the genetic change and it is not yet clear to what degree individuals with a single (heterozygous) mutation are predisposed to developing Parkinsonian features. A better understanding of the mode of inheritance, penetrance, and carrier frequency is needed to interpret the significance of single (heterozygous) mutations. Apparently autosomal dominant forms of inheritance have also been noted [Criscuolo et al 2006]. Absence of a PINK1 mutation on one or both alleles cannot completely exclude the diagnosis of the PINK1 type of young-onset Parkinson disease. Testing StrategyTo confirm/establish the diagnosis in a proband. Molecular genetic testing:Single gene testing. One strategy for molecular diagnosis of a proband suspected of having PINK1 type of young-onset Parkinson disease is sequence analysis, followed (when appropriate) by deletion/duplication analysis, of PINK1. Identification of disease-causing mutations on both PINK1 alleles (i.e., the individual is homozygous for the same disease-causing allele or a compound-heterozygote for two different disease-causing alleles) is required. (see Molecular Genetic Testing, Interpretation of test results)Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having PINK1 type of young-onset Parkinson disease is use of a multi-gene panel. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are probably not at significant risk of developing the disorder (see Genetically Related Disorders)Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies requires prior identification of the disease-causing mutations in the family. Genetically Related (Allelic) DisordersA few reports suggest that PINK1 mutations could manifest in heterozygotes and result in autosomal dominant Parkinson disease or constitute a risk factor for Parkinson disease [Criscuolo et al 2006]. In a Parkinson disease study by Marongiu et al [2008], the average age at onset in persons with a single PINK1 pathologic allelic variant (i.e., heterozygotes) was 52 years. However, whether and to what extent a single mutation may be pathogenic remains to be proven.
Women and men are affected equally. Age at onset is highly variable, even in individuals with the same mutation [Hedrich et al 2006]; onset is usually in the third or fourth decade [Bonifati et al 2005, Ishihara-Paul et al 2008, Marongiu et al 2008, Valente & Ferraris 2010]. In the study by Marongiu et al [2008] the average age at onset in those with two PINK1 mutations was 41 years. ...
Natural HistoryWomen and men are affected equally. Age at onset is highly variable, even in individuals with the same mutation [Hedrich et al 2006]; onset is usually in the third or fourth decade [Bonifati et al 2005, Ishihara-Paul et al 2008, Marongiu et al 2008, Valente & Ferraris 2010]. In the study by Marongiu et al [2008] the average age at onset in those with two PINK1 mutations was 41 years. Bradykinesia and tremor are the most common presenting signs. In some individuals the symptoms at onset are symmetric. Dystonia and hyperreflexia may also be present [Bonifati et al 2005]. In addition to parkinsonism, individuals with the PINK1 type of young-onset Parkinson disease may be prone to psychiatric involvement. Abnormal behavior and/or psychiatric manifestations, in particular depression and anxiety, occur in about 30% and 15% of affected individuals, respectively. Other features include hallucinations and dementia [Kasten et al 2010]. Overall, the clinical signs at examination are also variable. On average, the response to levodopa is better than in other forms of Parkinson disease [Valente & Ferraris 2010]; however, the incidence of levodopa-induced dyskinesias may be greater in individuals with PINK1-associated young-onset Parkinson disease than in those with parkinsonism of different etiologies [Nishioka et al 2009]. The disease is slowly progressive. Neuroimaging. CT and MRI neuroimaging are usually normal. MR spectroscopy (MRS) demonstrated raised myoinositol levels in the basal ganglia of the two individuals who were imaged, reflecting possible astroglial proliferation [Prestel et al 2008].For asymptomatic heterozygotes with a single mutant PINK1 allele, voxel-based morphometry revealed an increase of putaminal and pallidal gray matter volume –findings generally similar to those in the parkin type of young-onset Parkinson disease [Binkofski et al 2007, Reetz et al 2010]. Reduced presynaptic striatal uptake was seen on 18F-dopa-PET studies in four homozygous individuals and three asymptomatic heterozygous relatives: 85% reduction and 20%-30% reduction in uptake, respectively [Khan et al 2002]. In another study PET imaging with a dopamine D2 receptor ligand 11C-raclopride in one affected case with a homozygous missense mutation revealed that postsynaptic 11C-raclopride uptake was normal in the bilateral putamen [Yamashita et al 2008]. Neuropathology. Neuropathologic data in PINK1 mutation carriers are limited [Poulopoulos et al 2012]. Brain autopsy data are available only for one compound heterozygote mutation carrier (deletion and a splicing mutation in exon 7) with onset of disease at age 31 [Samaranch et al 2010, Poulopoulos et al 2012]. Pathologic study revealed significant presence of Lewy bodies and neuronal loss in the substantia nigra pars compacta with sparing of the locus coeruleus, which would be atypical for idiopathic Parkinson disease (PD). The brain stem reticular formation and the nucleus basalis of Meynert were also affected. There were no tau- or TDP43-positive inclusions. In a PD brain bank study Gandhi et al [2006] identified four individuals with PD and heterozygous PINK1 mutations who showed pathologic findings consistent with classical PD with Lewy bodies distributed in the brain stem and cortical areas, and neuronal loss affecting the substantia nigra pars compacta and neurofibrillary tangles stage I to V.
No correlation between the type of mutation and age at onset, clinical presentation, or disease progression has yet been observed. ...
Genotype-Phenotype CorrelationsNo correlation between the type of mutation and age at onset, clinical presentation, or disease progression has yet been observed. Individuals with both PINK1 and mitochondrial DNA (mtDNA) mutations who have very early onset of symptoms have been reported [Piccoli et al 2008]. It is possible that the combination of mutations in both genes may have accelerated the disease onset.
Parkinson disease multi-gene panels may include testing for a number of the genes associated with disorders discussed in this section. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest....
Differential DiagnosisParkinson disease multi-gene panels may include testing for a number of the genes associated with disorders discussed in this section. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest.Clinically, the PINK1 type of young-onset Parkinson disease and idiopathic Parkinson disease are difficult to differentiate (see Parkinson Disease Overview). More than 80% of individuals with Parkinson disease have no family history of the disorder. Several monogenic forms account for some of the cases with a positive family history. PARK2-related juvenile parkinsonism is more common than PINK1 type of young-onset Parkinson disease [Marongiu et al 2008]. The clinical findings in individuals with mutations in PARK2 and PINK1 are indistinguishable.Another disorder in the differential diagnosis is the DJ1- type of young-onset Parkinson disease, which also presents as early-onset disorder with a phenotype overall similar to that of the PINK1 type of young-onset Parkinson disease [Bonifati et al 2003, Li et al 2005].For individuals with juvenile-onset Parkinson disease, especially those with prominent dystonia, dopa-responsive dystonia should be considered, for example GTP cyclohydrolase 1-deficient dopa-responsive dystonia, caused by mutations in the GTP cyclohydrolase I gene (GCH1).Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with the PINK1 type of young-onset Parkinson disease, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with the PINK1 type of young-onset Parkinson disease, the following evaluations are recommended:Assessment for presence/severity atypical signs using the Unified Parkinson’s Disease Rating Scale (UPDRS) rating scale [Goetz et al 2008]Evaluation of the degree of response to treatment and its potential complicationsAssessment for cognitive or behavioral problemsMedical genetics consultationTreatment of ManifestationsTo date, the treatment of PINK1 type of young-onset Parkinson disease is not different from that of idiopathic Parkinson disease and no specific guidelines or recommendations have been developed.Individuals with PINK1 type of young-onset Parkinson disease have a mild form of Parkinson disease that responds well to levodopa and to other dopaminergic agonists.Response is usually significant and is sustained for low doses of levodopa even after long disease duration. The response may be even better in PINK1 type of young-onset Parkinson disease than in idiopathic Parkinson disease [Valente & Ferraris 2010].The major problem is the early occurrence of severe levodopa-induced dyskinesias (abnormal involuntary movements) and fluctuations. Fluctuations can be reduced by the combination of dopamine therapies with low doses of levodopa. The use of deep brain stimulation (DBS) in PINK1 type Parkinson disease has been described [Moro et al 2008, Johansen et al 2011]. Prevention of Secondary ComplicationsTo reduce or delay side effects, levodopa dosage should not exceed the level required for satisfactory clinical response.SurveillanceNeurologic follow up every three to 12 months to modify treatment as needed is appropriate.Agents/Circumstances to AvoidNeuroleptic treatment may exacerbate parkinsonism.Evaluation of Relatives at RiskOwing to the absence of preventive treatment or measures, presymptomatic genetic diagnosis is not medically justified.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. PINK1 Type of Young-Onset Parkinson Disease : Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPARK6PINK11p36.12Serine/threonine-protein kinase PINK1, mitochondrialParkinson's disease Mutation Database PD mutation databasePINK1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for PINK1 Type of Young-Onset Parkinson Disease (View All in OMIM) View in own window 605909PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET; PARK6 608309PTEN-INDUCED PUTATIVE KINASE 1; PINK1Normal allelic variants. PINK1 contains eight exons (NM_032409.2) spanning about 18 kb. Abnormal allelic variants. Changes have been identified in the homozygous, compound-heterozygous, and heterozygous state. Mutations include missense, nonsense, and splice site mutations and small insertions. Rarely, exonic, multiexonic [Li et al 2005, Cazeneuve et al 2009], and whole-gene deletions [Marongiu et al 2007] have been described. Normal gene product. The gene encodes a 581-amino acid serine/threonine kinase, PTEN-induced putative kinase 1 (NP_115785.1). This kinase is located in the mitochondria spanning the outer mitochondrial membrane with the C-terminal kinase domain facing the cytoplasm and the N-terminal end inside the mitochondria. PINK1 presumably exerts its neuroprotective effect by phosphorylating specific mitochondrial proteins and, in turn, modulating their functions [Sim et al 2006]. Thereby, the PINK1 promotes elimination of dysfunctional mitochondria by autophagy. Notably, PINK1 and parkin have been mapped to a shared pathway with PINK1 acting upstream of parkin where PINK1 can initiate the translocation of parkin to mitochondria [Hoepken et al 2007, Gandhi et al 2009, Narendra et al 2010, Vives-Bauza et al 2010].Abnormal gene product. Most of the known mutations are localized within the serine/threonine kinase domain of PINK1 as expected [Valente et al 2004a]. PINK1 mutations or PINK1 silencing result in reduced mtDNA levels, defective ATP production, impaired mitochondrial calcium handling, and increased free radical generation. This in turn results in a fall in mitochondrial membrane potential and an increased susceptibility to apoptosis in neuronal cells, animal models, and patient-derived fibroblasts [Valente et al 2004a, Gegg et al 2009, Abramov et al 2011].Overexpression of the parkin protein can rescue the effects of a PINK1 mutation in Drosophila and mammalian cells. Studies in fibroblasts from human Parkinson disease patients revealed impaired ubiquitination of mitofusins and confirmed the link between the PINK1 and Parkin pathways [Rakovic et al 2010, Rakovic et al 2011, Seibler et al 2011].