PINK1 Phosphorylates MIC60/Mitofilin to Control Structural Plasticity of Mitochondrial Crista Junctions.

Mitochondrial crista structure partitions vital cellular reactions and is precisely regulated by diverse cellular signals. Here, we show that, in Drosophila, mitochondrial cristae undergo dynamic remodeling among distinct subcellular regions and the Parkinson's disease (PD)-linked Ser/Thr kinase PINK1 participates in their regulation. Mitochondria increase crista junctions and numbers in selective subcellular areas, and this remodeling requires PINK1 to phosphorylate the inner mitochondrial membrane protein MIC60/mitofilin, which stabilizes MIC60 oligomerization. Expression of MIC60 restores crista structure and ATP levels of PINK1-null flies and remarkably rescues their behavioral defects and dopaminergic neurodegeneration. In an extension to human relevance, we discover that the PINK1-MIC60 pathway is conserved in human neurons, and expression of several MIC60 coding variants in the mitochondrial targeting sequence found in PD patients in Drosophila impairs crista junction formation and causes locomotion deficits. These findings highlight the importance of maintenance and plasticity of crista junctions to cellular homeostasis in vivo.

Basic Science in Movement Disorders: Fueling the Engine of Translation into Clinical Practice.

Basic Science is crucial for the advancement of clinical care for Movement Disorders. Here, we provide brief updates on how basic science is important for understanding disease mechanisms, disease prevention, disease diagnosis, development of novel therapies and to establish the basis for personalized medicine. We conclude the viewpoint by a call to action to further improve interactions between clinician and basic scientists. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Impaired gut barrier integrity and reduced colonic expression of free fatty acid receptors in patients with Parkinson's disease.

BACKGROUND: Altered gut metabolites, especially short-chain fatty acids (SCFAs), in feces and plasma are observed in patients with Parkinson's disease (PD). OBJECTIVE: We aimed to investigate the colonic expression of two SCFA receptors, free fatty acid receptor (FFAR)2 and FFAR3, and gut barrier integrity in patients with PD and correlations with clinical severity. METHODS: In this retrospective study, colonic biopsy specimens were collected from 37 PD patients and 34 unaffected controls. Of this cohort, 31 participants (14 PD, 17 controls) underwent a series of colon biopsies. Colonic expression of FFAR2, FFAR3, and the tight junction marker ZO-1 were assayed by immunofluorescence staining. The You Only Look Once (version 8, YOLOv8) algorithm was used for automated detection and segmentation of immunostaining signal. PD motor function was assessed with the Movement Disorder Society (MDS)-Unified Parkinson's Disease Rating Scale (UPDRS), and constipation was assessed using Rome-IV criteria. RESULTS: Compared with controls, PD patients had significantly lower colonic expression of ZO-1 (p < 0.01) and FFAR2 (p = 0.01). On serial biopsy, colonic expression of FFAR2 and FFAR3 was reduced in the pre-motor stage before PD diagnosis (both p < 0.01). MDS-UPDRS motor scores did not correlate with colonic marker levels. Constipation severity negatively correlated with colonic ZO-1 levels (r = -0.49, p = 0.02). CONCLUSIONS: Colonic expression of ZO-1 and FFAR2 is lower in PD patients compared with unaffected controls, and FFAR2 and FFAR3 levels decline in the pre-motor stage of PD. Our findings implicate a leaky gut phenomenon in PD and reinforce that gut metabolites may contribute to the process of PD.

The HSP40 family chaperone isoform DNAJB6b prevents neuronal cells from tau aggregation.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disorder with clinical presentations of progressive cognitive and memory deterioration. The pathologic hallmarks of AD include tau neurofibrillary tangles and amyloid plaque depositions in the hippocampus and associated neocortex. The neuronal aggregated tau observed in AD cells suggests that the protein folding problem is a major cause of AD. J-domain-containing proteins (JDPs) are the largest family of cochaperones, which play a vital role in specifying and directing HSP70 chaperone functions. JDPs bind substrates and deliver them to HSP70. The association of JDP and HSP70 opens the substrate-binding domain of HSP70 to help the loading of the clients. However, in the initial HSP70 cycle, which JDP delivers tau to the HSP70 system in neuronal cells remains unclear. RESULTS: We screened the requirement of a diverse panel of JDPs for preventing tau aggregation in the human neuroblastoma cell line SH-SY5Y by a filter retardation method. Interestingly, knockdown of DNAJB6, one of the JDPs, displayed tau aggregation and overexpression of DNAJB6b, one of the isoforms generated from the DNAJB6 gene by alternative splicing, reduced tau aggregation. Further, the tau bimolecular fluorescence complementation assay confirmed the DNAJB6b-dependent tau clearance. The co-immunoprecipitation and the proximity ligation assay demonstrated the protein-protein interaction between tau and the chaperone-cochaperone complex. The J-domain of DNAJB6b was critical for preventing tau aggregation. Moreover, reduced DNAJB6 expression and increased tau aggregation were detected in an age-dependent manner in immunohistochemical analysis of the hippocampus tissues of a mouse model of tau pathology. CONCLUSIONS: In summary, downregulation of DNAJB6b increases the insoluble form of tau, while overexpression of DNAJB6b reduces tau aggregation. Moreover, DNAJB6b associates with tau. Therefore, this study reveals that DNAJB6b is a direct sensor for its client tau in the HSP70 folding system in neuronal cells, thus helping to prevent AD.

Phenotypic Heterogeneity in Patients with Mutations in the Mitochondrial Complex I Assembly Gene NDUFAF5.

BACKGROUND: Rare mutations in NADH:ubiquinone oxidoreductase complex assembly factor 5 (NDUFAF5) are linked to Leigh syndrome. OBJECTIVE: We aimed to describe clinical characteristics and functional findings in a patient cohort with NDUFAF5 mutations. METHODS: Patients with biallelic NDUFAF5 mutations were recruited from multi-centers in Taiwan. Clinical, laboratory, radiological, and follow-up features were recorded and mitochondrial assays were performed in patients' skin fibroblasts. RESULTS: Nine patients from seven unrelated pedigrees were enrolled, eight homozygous for c.836 T > G (p.Met279Arg) in NDUFAF5 and one compound heterozygous for p.Met279Arg. Onset age had a bimodal distribution. The early-onset group (age <3 years) presented with psychomotor delay, seizure, respiratory failure, and hyponatremia. The late-onset group (age ≥5 years) presented with normal development, but slowly progressive dystonia. Combing 25 previously described patients, the p.Met279Arg variant was exclusively identified in Chinese ancestry. Compared with other groups, patients with late-onset homozygous p.Met279Arg were older at onset (P = 0.008), had less developmental delay (P = 0.01), less hyponatremia (P = 0.01), and better prognosis with preserved ambulatory function into early adulthood (P = 0.01). Bilateral basal ganglia necrosis was a common radiological feature, but brainstem and spinal cord involvement was more common with early-onset patients (P = 0.02). A modifier gene analysis showed higher concomitant mutation burden in early-versus late-onset p.Met279Arg homozygous cases (P = 0.04), consistent with more impaired mitochondrial function in fibroblasts from an early-onset case than a late-onset patient. CONCLUSIONS: The p.Met279Arg variant is a common mutation in our population with phenotypic heterogeneity and divergent prognosis based on age at onset. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort.

BACKGROUND: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. OBJECTIVE: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. METHODS: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. RESULTS: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. CONCLUSIONS: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Blood neurofilament light chain as a surrogate marker for dystonia.

BACKGROUND AND PURPOSE: Dystonia is a heterogeneous movement disorder, and it remains unclear whether neurodegeneration is involved. Neurofilament light chain (NfL) is a biosignature of neurodegeneration. We aimed to investigate whether plasma NfL levels were elevated and associated with disease severity in patients with dystonia. METHOD: We enrolled 231 unrelated dystonia patients (isolated dystonia n = 203; combined dystonia n = 28) and 54 healthy controls from movement disorder clinics. Clinical severity was evaluated using the Fahn Marsden Dystonia Rating Scale, the Unified Dystonia Rating Scale, and the Global Dystonia Rating Scale. Blood NfL levels were measured by single-molecule array. RESULTS: Plasma NfL levels were significantly higher in those with generalized dystonia compared to those with focal dystonia (20.1 ± 8.8 vs. 11.7 ± 7.2 pg/mL; p = 0.01) or controls (p < 0.01), while the level was comparable between the focal dystonia group and controls (p = 0.08). Furthermore, the dystonia combined with parkinsonism group had higher NfL levels than the isolated dystonia group (17.4 ± 6.2 vs. 13.5 ± 7.5 pg/mL; p = 0.04). Notably, whole-exome sequencing was performed in 79 patients and two patients were identified as having likely pathogenic variants: one had a heterozygous c.122G>A (p.R41H) variant in THAP1 (DYT6) and the other carried a c.1825G>A (p.D609N) substitution in ATP1A3 (DYT12). No significant correlation was found between plasma NfL levels and dystonia rating scores. CONCLUSION: Plasma NfL levels are elevated in patients with generalized dystonia and dystonia combined with parkinsonism, suggesting that neurodegeneration is involved in the disease process of this subgroup of patients.

Neural Basis of Somatosensory Spatial and Temporal Discrimination in Humans: The Role of Sensory Detection.

While detecting somatic stimuli from the external environment, an accurate determination of their spatial and temporal properties is essential for human behavior. Whether and how detection relates to human capacity for somatosensory spatial discrimination (SD) and temporal discrimination (TD) remains unclear. Here, participants underwent functional magnetic resonance imaging scanning when simply detecting vibrotactile stimuli of the leg, judging their location (SD), or deciding their number in time (TD). By conceptualizing tactile discrimination as consisting of detection and determination processes, we found that tactile detection elicited activation specifically involved in SD within the right inferior and superior parietal lobules, 2 regions previously implicated in the control of spatial attention. These 2 regions remained activated in the determination process, during which functional connectivity between these 2 regions predicted individual SD ability. In contrast, tactile detection produced little activation specifically related to TD. Participants' TD ability was implemented in brain regions implicated in coding temporal structures of somatic stimuli (primary somatosensory cortex) and time estimation (anterior cingulate, pre-supplementary motor area, and putamen). Together, our findings indicate a close link between somatosensory detection and SD (but not TD) at the neural level, which aids in explaining why we can promptly respond toward detected somatic stimuli.

Gut-oriented disease modifying therapy for Parkinson's disease.

Neuropathology studies have shown that the pathognomonic feature of Parkinson's disease (PD), one of the most common neurodegenerative disorders, may start from the gut enteric nervous system and then spread to the central dopaminergic neurons through the gut-brain axis. With the advent of metagenomic sequencing and metabolomic analysis, a plethora of evidence has revealed different gut microbiomes and gut metabolites in patients with PD compared with unaffected controls. Currently, although dopaminergic treatments and deep brain stimulation can provide some symptomatic benefits for motor symptoms of the disease, their long-term use is problematic. A mechanism-targeted therapy to halt the neurodegeneration is lacking. The recently observed gut microenvironmental changes in the early stages of the disease play a vital role in the PD pathogenesis. Patients whose disease begins in the gut may benefit most from interventions that target the gut microenvironments. In this review, we will summarize the current studies demonstrating multifunctional roles of gut microbiota in the gut-brain axis of PD and the currently available evidence for targeting the gut microbiota as a novel approach to potential disease-modifying therapy in PD.

Mild Chronic Colitis Triggers Parkinsonism in LRRK2 Mutant Mice Through Activating TNF-α Pathway.

BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) is a common risk gene for Parkinson's disease (PD) and inflammatory bowel disorders. However, the penetrance of the most prevalent LRRK2 mutation, G2019S, is <50%. Factors other than genetic mutations are needed in PD process. OBJECTIVES: To examine whether and how gut inflammation may act as an environmental trigger to neurodegeneration in PD. METHODS: A mild and chronic dextran sodium sulfate (DSS)-induced colitis mice model harboring LRRK2 G2019S mutation was established. The colitis severity, immune responses, locomotor function, dopaminergic neuron, and microglia integrity were compared between littermate controls, transgenic LRRK2 wild type (WT), and LRRK2 G2019S mice. RESULTS: The LRRK2 G2019S mice are more vulnerable to DSS-induced colitis than littermate controls or LRRK2 WT animals with increased intestinal expressions of pattern-recognition receptors, including toll-like receptors (TLRs), nuclear factor (NF)-κB activation, and pro-inflammatory cytokines secretion, especially tumor necrosis factor (TNF)-α. Notably, the colonic expression of α-synuclein was significantly increased in LRRK2 G2019S colitis mice. We subsequently observed more aggravated locomotor defect, microglia activation, and dopaminergic neuron loss in LRRK2 G2019S colitis mice than control animals. Treatment with anti-TNF-α monoclonal antibody, adalimumab, abrogated both gut and neuroinflammation, mitigated neurodegeneration, and improved locomotor function in LRRK2 G2019S colitis mice. Finally, we validated increased colonic expressions of LRRK2, TLRs, and NF-κB pathway proteins and elevated plasma TNF-α level in PD patients compared to controls, especially in those with LRRK2 risk variants. CONCLUSIONS: Our findings demonstrate that chronic colitis promotes parkinsonism in genetically susceptible mice and TNF-α plays a detrimental role in the gut-brain axis of PD. © 2021 International Parkinson and Movement Disorder Society.

Gut microenvironmental changes as a potential trigger in Parkinson's disease through the gut-brain axis.

Parkinson's disease (PD) is the second most common neurodegenerative disease attributed to the synergistic effects of genetic risk and environmental stimuli. Although PD is characterized by motor dysfunction resulting from intraneuronal alpha-synuclein accumulations, termed Lewy bodies, and dopaminergic neuronal degeneration in the substantia nigra, multiple systems are involved in the disease process, resulting in heterogenous clinical presentation and progression. Genetic predisposition to PD regarding aberrant immune responses, abnormal protein aggregation, autophagolysosomal impairment, and mitochondrial dysfunction leads to vulnerable neurons that are sensitive to environmental triggers and, together, result in neuronal degeneration. Neuropathology studies have shown that, at least in some patients, Lewy bodies start from the enteric nervous system and then spread to the central dopaminergic neurons through the gut-brain axis, suggesting the contribution of an altered gut microenvironment in the pathogenesis of PD. A plethora of evidence has revealed different gut microbiomes and gut metabolites in patients with PD compared to unaffected controls. Chronic gut inflammation and impaired intestinal barrier integrity have been observed in human PD patients and mouse models of PD. These observations led to the hypothesis that an altered gut microenvironment is a potential trigger of the PD process in a genetically susceptible host. In this review, we will discuss the complex interplay between genetic factors and gut microenvironmental changes contributing to PD pathogenesis.

Amantadine treatment and delayed onset of levodopa-induced dyskinesia in patients with early Parkinson's disease.

BACKGROUND AND PURPOSE: Levodopa-induced dyskinesia (LID) is a common motor complication in patients with Parkinson's disease (PD). Although amantadine is indicated for LID treatment, it is uncertain whether early treatment with amantadine reduces the risk of LID in patients with PD. We aimed to evaluate the association between amantadine treatment and LID onset in patients with early-stage PD. METHODS: This was a hospital-based retrospective cohort study that used electronic medical records from January 1, 2009 to October 31, 2016. The effect of amantadine on LID onset was compared with those of anticholinergics and monoamine oxidase type B inhibitors in patients with PD. Propensity-score weighting and landmark analysis were used to reduce potential confounding. The time to LID onset was analyzed using Cox models. Sensitivity analyses were performed to determine the robustness of the results. RESULTS: The analyses included 807, 661, and 518 patients at 6-, 12-, and 18-month landmark points, respectively. Amantadine use was associated with delayed LID onset in the 6- and 12-month landmark analyses, with adjusted hazard ratios of 0.65 (95% confidence interval [CI] = 0.49-0.86) and 0.64 (95% CI = 0.47-0.88), respectively. Sensitivity analysis findings were comparable to those of the main analysis. CONCLUSIONS: Early treatment with amantadine may delay LID onset more than treatment with other symptomatic agents. Further studies are needed to elucidate the mechanism of amantadine in LID onset delay and to validate our findings.

COQ2 and SNCA polymorphisms interact with environmental factors to modulate the risk of multiple system atrophy and subtype disposition.

BACKGROUND AND PURPOSE: Multiple system atrophy (MSA) has no definitive genetic or environmental (G-E) risk factors, and the integrated effect of these factors on MSA etiology remains unknown. This study was undertaken to investigate the integrated effect of G-E factors associated with MSA and its subtypes, MSA-P and MSA-C. METHODS: A consecutive case-control study was conducted at two medical centers, and the interactions between genotypes of five previously reported susceptible single nucleotide polymorphisms (SNPs; SNCA_rs3857059, SNCA_rs11931074, COQ2_rs148156462, EDN1_rs16872704, MAPT_rs9303521) and graded exposure (never, ever, current) of four environmental factors (smoking, alcohol, drinking well water, pesticide exposure) were analyzed by a stepwise logistic regression model. RESULTS: A total of 207 MSA patients and 136 healthy controls were enrolled. In addition to SNP COQ2_rs148156462 (TT), MSA risk was correlated with G-E interactions, including COQ2_rs148156462 (Tc) × pesticide nonexposure, COQ2_rs148156462 (TT) × current smokers, SNCA_rs11931074 (tt) × alcohol nonusers, and SNCA_rs11931074 (GG) × well water nondrinkers (all p < 0.01), with an area under the receiver operating characteristic curve (AUC) of 0.804 (95% confidence interval [CI] = 0.671-0.847). Modulated risk of MSA-C, with MSA-P as a control, correlated with COQ2_rs148156462 (TT) × alcohol nondrinkers, SNCA_rs11931074 (GG) × well water ever drinkers, SNCA_rs11931074 (Gt) × well water never drinkers, and SNCA_rs3857059 (gg) × pesticide nonexposure (all p < 0.05), with an AUC of 0.749 (95% CI = 0.683-0.815). CONCLUSIONS: Certain COQ2 and SNCA SNPs interact with common environmental factors to modulate MSA etiology and subtype disposition. The mechanisms underlying the observed correlation between G-E interactions and MSA etiopathogenesis warrant further investigation.

Investigating DYT1 in a Taiwanese dystonia cohort.

BACKGROUND/PURPOSE: A heterozygous three-nucleotide (GAG) in-frame deletion in the TOR1A gene causes the rare disease, dystonia (DYT1), which typically presents as focal limb dystonia during adolescence, then spreads to other limbs. This study investigated the frequency and clinical features of DYT1 in a Taiwanese dystonia cohort. METHODS: We performed targeted next generation sequencing in 318 patients with primary dystonia. We identified one DYT1 family with various types of dystonia, and we described the clinical presentations observed in this family during a 30-year follow-up. We compared the clinical characteristics to those reported in previous studies on DYT1 from 2000 to 2020. RESULTS: Among 318 patients, we identified only one DYT1 patient (0.3%) with an autosomal dominant family history of dystonia. The proband was a 43-year-old man that experienced progressive onset of focal lower limb dystonia from age 11 years. The disease spread caudal-rostrally to the upper limbs and cervical muscles. Prominent cervical dystonia was noted during follow-up, which was an atypical presentation of DYT1. Clinical assessments of other family members showed intrafamily variability. The proband's father and an affected sibling demonstrated only mild right-hand writer's cramp. A systematic review of previously reported DTY1 cases showed that Asian patients had a higher frequency of cervical dystonia (44.8%) than groups of Ashkenazi Jews (35%) and Non-Jewish Caucasians (30.5%) (P = 0.04). CONCLUSION: Our findings revealed that DYT1 is rare in a Taiwanese dystonia cohort. The presentation of marked cervical dystonia could be the main feature of Asian patients with DYT1.

Sonogenetic-Based Neuromodulation for the Amelioration of Parkinson's Disease.

Sonogenetics is a promising strategy allowing the noninvasive and selective activation of targeted neurons in deep brain regions; nevertheless, its therapeutic outcome for neurodegeneration diseases that need long-term treatment remains to be verified. We previously enhanced the ultrasound (US) sensitivity of targeted cells by genetic modification with an engineered auditory-sensing protein, mPrestin (N7T, N308S). In this study, we expressed mPrestin in the dopaminergic neurons of the substantia nigra in Parkinson's disease (PD) mice and used 0.5 MHz US for repeated and localized brain stimulation. The mPrestin expression in dopaminergic neurons persisted for at least 56 days after a single shot of adeno-associated virus, suggesting that the period of expression was long enough for US treatment in mice. Compared to untreated mice, US stimulation ameliorated the dopaminergic neurodegeneration 10-fold and mitigated the PD symptoms of the mice 4-fold, suggesting that this sonogenetic strategy has the clinical potential to treat neurodegenerative diseases.

A Double-Blind, Randomized, Controlled Trial of Lovastatin in Early-Stage Parkinson's Disease.

BACKGROUND: Recent evidence indicates that lipophilic statins have a neuroprotective benefit in animal models of Parkinson's disease (PD). The objective of this study was to evaluate whether lovastatin has the potential to slow motor symptom progression in patients with early-stage PD. METHODS: This double-blind, randomized, placebo-controlled trial enrolled 77 patients with early-stage PD between May 23, 2017, and July 12, 2018, with follow-up ending September 1, 2019. Lovastatin 80 mg/day or placebo with 1:1 randomization was administered for 48 weeks. Mean change in the parts I-III scores of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), changes in the striatal dopamine uptake ratio measured by 18 F-dopa PET scan, and changes in PD medications between baseline and the week 48 visit were measured. RESULTS: Of the 77 randomized patients, 70 (90.9%) completed the study. There was a slightly beneficial trend of the MDS-UPDRS motor score in the lovastatin group (-3.18 ± 5.50) compared with the placebo group (-0.50 ± 6.11); P = 0.14 adjusted for age, sex, disease duration, and baseline LEDD. Mean percentage change in the striatal 18 F-dopa uptake ratio deteriorated less in the lovastatin group than in the placebo group on the dominant side of caudate (1.2% ± 7.3% vs -7.1% ± 8.2%, P < 0.01) and putamen (2.3% ± 7.1% vs -6.4% ± 8.1%, P < 0.01). We found no between-group differences in the change in part I or part II MDS-UPDRS scores. Lovastatin was generally well tolerated. CONCLUSIONS: Lovastatin treatment in patients with early-stage PD was associated with a trend of less motor symptom worsening and was well tolerated. A future larger long-term follow-up study is needed to confirm our findings. © 2021 International Parkinson and Movement Disorder Society.

Clinical and functional characterization of a novel STUB1 frameshift mutation in autosomal dominant spinocerebellar ataxia type 48 (SCA48).

BACKGROUND: Heterozygous pathogenic variants in STUB1 are implicated in autosomal dominant spinocerebellar ataxia type 48 (SCA48), which is a rare familial ataxia disorder. We investigated the clinical, genetic and functional characteristics of STUB1 mutations identified from a Taiwanese ataxia cohort. METHODS: We performed whole genome sequencing in a genetically undiagnosed family with an autosomal dominant ataxia syndrome. Further Sanger sequencing of all exons and intron-exon boundary junctions of STUB1 in 249 unrelated patients with cerebellar ataxia was performed. The pathogenicity of the identified novel STUB1 variant was investigated. RESULTS: We identified a novel heterozygous frameshift variant, c.832del (p.Glu278fs), in STUB1 in two patients from the same family. This rare mutation is located in the U-box of the carboxyl terminus of the Hsc70-interacting protein (CHIP) protein, which is encoded by STUB1. Further in vitro experiments demonstrated that this novel heterozygous STUB1 frameshift variant impairs the CHIP protein's activity and its interaction with the E2 ubiquitin ligase, UbE2D1, leading to neuronal accumulation of tau and α-synuclein, caspase-3 activation, and promoting cellular apoptosis through a dominant-negative pathogenic effect. The in vivo study revealed the influence of the CHIP expression level on the differentiation and migration of cerebellar granule neuron progenitors during cerebellar development. CONCLUSIONS: Our findings provide clinical, genetic, and a mechanistic insight linking the novel heterozygous STUB1 frameshift mutation at the highly conserved U-box domain of CHIP as the cause of autosomal dominant SCA48. Our results further stress the importance of CHIP activity in neuronal protein homeostasis and cerebellar functions.

Mitochondrial UQCRC1 mutations cause autosomal dominant parkinsonism with polyneuropathy.

Parkinson's disease is a neurodegenerative disorder with a multifactorial aetiology. Nevertheless, the genetic predisposition in many families with multi-incidence disease remains unknown. This study aimed to identify novel genes that cause familial Parkinson's disease. Whole exome sequencing was performed in three affected members of the index family with a late-onset autosomal-dominant parkinsonism and polyneuropathy. We identified a novel heterozygous substitution c.941A>C (p.Tyr314Ser) in the mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene, which co-segregates with disease within the family. Additional analysis of 699 unrelated Parkinson's disease probands with autosomal-dominant Parkinson's disease and 1934 patients with sporadic Parkinson's disease revealed another two variants in UQCRC1 in the probands with familial Parkinson's disease, c.931A>C (p.Ile311Leu) and an allele with concomitant splicing mutation (c.70-1G>A) and a frameshift insertion (c.73_74insG, p.Ala25Glyfs*27). All substitutions were absent in 1077 controls and the Taiwan Biobank exome database from healthy participants (n = 1517 exomes). We then assayed the pathogenicity of the identified rare variants using CRISPR/Cas9-based knock-in human dopaminergic SH-SY5Y cell lines, Drosophila and mouse models. Mutant UQCRC1 expression leads to neurite degeneration and mitochondrial respiratory chain dysfunction in SH-SY5Y cells. UQCRC1 p.Tyr314Ser knock-in Drosophila and mouse models exhibit age-dependent locomotor defects, dopaminergic neuronal loss, peripheral neuropathy, impaired respiratory chain complex III activity and aberrant mitochondrial ultrastructures in nigral neurons. Furthermore, intraperitoneal injection of levodopa could significantly improve the motor dysfunction in UQCRC1 p.Tyr314Ser mutant knock-in mice. Taken together, our in vitro and in vivo studies support the functional pathogenicity of rare UQCRC1 variants in familial parkinsonism. Our findings expand an additional link of mitochondrial complex III dysfunction in Parkinson's disease.

Detection and Classification of Stroke Gaits by Deep Neural Networks Employing Inertial Measurement Units.

This paper develops Deep Neural Network (DNN) models that can recognize stroke gaits. Stroke patients usually suffer from partial disability and develop abnormal gaits that can vary widely and need targeted treatments. Evaluation of gait patterns is crucial for clinical experts to make decisions about the medication and rehabilitation strategies for the stroke patients. However, the evaluation is often subjective, and different clinicians might have different diagnoses of stroke gait patterns. In addition, some patients may present with mixed neurological gaits. Therefore, we apply artificial intelligence techniques to detect stroke gaits and to classify abnormal gait patterns. First, we collect clinical gait data from eight stroke patients and seven healthy subjects. We then apply these data to develop DNN models that can detect stroke gaits. Finally, we classify four common gait abnormalities seen in stroke patients. The developed models achieve an average accuracy of 99.35% in detecting the stroke gaits and an average accuracy of 97.31% in classifying the gait abnormality. Based on the results, the developed DNN models could help therapists or physicians to diagnose different abnormal gaits and to apply suitable rehabilitation strategies for stroke patients.

Updates on the Genetics of Parkinson's Disease: Clinical Implications and Future Treatment.

Parkinson' disease (PD) is a common neurodegenerative disease with the pathological hallmark of alpha-synuclein aggregation within dopaminergic neurons. The etiology of PD comes from a complex interplay between genetic and environmental factors. Though most cases of PD are sporadic; a family history of PD is found in approximately 15% of patients. Pathogenic mutations are found in 5% to 10% of individuals with either familial or sporadic PD. In recent decades, because of the advent of next generation sequencing, more than 25 genes have been identified as causative genes in PD. These findings allow better understanding of the pathogenesis of PD, including aberrant alpha-synuclein homeostasis, defective mitochondrial functions, and impairment of the ubiquitin-proteasome and autophagy-lysosome pathways. Among the PD-causative genes, LRRK2 mutation is the most frequent mutation in autosomal dominant PD and Parkin mutation is prevalent in patients with autosomal recessive or early onset PD. Several genetic epidemiology studies in Asians have revealed a distinctive mutation spectrum from Western populations, reinforcing the importance of ethnic differences in PD. Proper genetic testing is recommended for patients with early onset, a strong family history, or associated red flag clinical features. Considering that clinical trials of disease-modifying therapy targeting patients with specific mutations are ongoing and we are in the era of precision medicine, this review highlights recent updates of genetic findings in patients with PD, focusing on Asian populations and practical recommendations for genetic testing. Keywords: Parkinson's disease, Genetics.