Parkin-mediated mitophagy has been studied extensively, but whether mutations in parkin contribute to Parkinson’s disease pathogenesis through alternative mechanisms remains unexplored. Using ...patient-derived dopaminergic neurons, we found that phosphorylation of parkin by Ca2+/calmodulin-dependent protein kinase 2 (CaMK2) at Ser9 leads to activation of parkin in a neuronal-activity-dependent manner. Activated parkin ubiquitinates synaptojanin-1, facilitating its interaction with endophilin A1 and synaptic vesicle recycling. Neurons from PD patients with mutant parkin displayed defective recycling of synaptic vesicles, leading to accumulation of toxic oxidized dopamine that was attenuated by boosting endophilin A1 expression. Notably, combined heterozygous parkin and homozygous PTEN-induced kinase 1 (PINK1) mutations led to earlier disease onset compared with homozygous mutant PINK1 alone, further underscoring a PINK1-independent role for parkin in contributing to disease. Thus, this study identifies a pathway for selective activation of parkin at human dopaminergic synapses and highlights the importance of this mechanism in the pathogenesis of Parkinson’s disease.
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•Neuronal activity triggers CaMK2-mediated activation of parkin at the synapse•Parkin ubiquitinates synaptojanin-1 to enhance its binding to endophilin A1•Parkin is dynamically recruited to synaptic vesicles to promote vesicle endocytosis•Toxic oxidized dopamine accumulates in mutant parkin DA neurons from PD patients
In brief, Song et al. found that neuronal activity triggers CaMK2-mediated activation of parkin and its recruitment to synaptic vesicles where parkin promotes binding of synaptojanin-1 to endophilin A1 and facilitates vesicle endocytosis. Mutant parkin leads to defective recycling of vesicles and accumulation of toxic oxidized dopamine in PD neurons.
Keppen–Lubinsky syndrome is caused by pathogenic variants in KCNJ6, which encodes the inwardly rectifying channel subfamily J6. The four confirmed cases reported to date were characterized by severe ...intellectual disability, global developmental delay, feeding difficulties, and dysmorphic features. All but one of the cases also had a severe form of lipodystrophy, resulting in tightly adherent facial skin and appearance of premature aging. Here, we describe a 36‐year‐old female with a de novo pathogenic variant in KCNJ6 (NM_002240.5: c.460G>T; p.(Gly154Cys)) presenting with mild intellectual disability, subtle dysmorphic features, obsessive–compulsive disorder, and an exaggerated startle response. This case indicates that KCNJ6‐related disorders should be considered in patients with less pronounced dysmorphic features and milder cognitive impairment, as well as in patients with startle disorders.
We describe here the case of a 36‐year‐old female with a de novo pathogenic variant in KCNJ6 (NM_002240.5: c.460G>T; p.(Gly154Cys)) presenting with mild intellectual disability, subtle dysmorphic features, obsessive–compulsive disorder, and an exaggerated startle response, thereby expanding the spectrum of KCNJ6‐related disorders to milder phenotypes.
Dystonia is a debilitating hyperkinetic movement disorder, which can be transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense, and missense variants in TSPOAP1, which ...encodes the active-zone RIM-binding protein 1 (RIMBP1), as a genetic cause of autosomal recessive dystonia in 7 subjects from 3 unrelated families. Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between dysfunction of the presynaptic active zone and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis.
Abstract
ATP5F1B is a subunit of the mitochondrial ATP synthase or complex V of the mitochondrial respiratory chain. Pathogenic variants in nuclear genes encoding assembly factors or structural ...subunits are associated with complex V deficiency, typically characterized by autosomal recessive inheritance and multisystem phenotypes. Movement disorders have been described in a subset of cases carrying autosomal dominant variants in structural subunits genes ATP5F1A and ATP5MC3.
Here, we report the identification of two different ATP5F1B missense variants (c.1000A>C; p.Thr334Pro and c.1445T>C; p.Val482Ala) segregating with early-onset isolated dystonia in two families, both with autosomal dominant mode of inheritance and incomplete penetrance. Functional studies in mutant fibroblasts revealed no decrease of ATP5F1B protein amount but severe reduction of complex V activity and impaired mitochondrial membrane potential, suggesting a dominant-negative effect.
In conclusion, our study describes a new candidate gene associated with isolated dystonia and confirms that heterozygous variants in genes encoding subunits of the mitochondrial ATP synthase may cause autosomal dominant isolated dystonia with incomplete penetrance, likely through a dominant-negative mechanism.
Nasca et al. identify a new candidate gene for dystonia, ATP5F1B, encoding a subunit of the mitochondrial ATP synthase (complex V). Likely pathogenic variants in ATP5F1B were associated with early-onset isolated dystonia in two independent families, both with an autosomal dominant mode of inheritance and incomplete penetrance.
GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine ...synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ((123)IN-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease.
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