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Parkinson’s disease (PD) is a common dyskinesia disease, the mitochondrial unfolded protein response (mtUPR) may be directly or indirectly involved in the occurrence and development of PD, although the exact mechanism is unclear. We established a dopaminergic neuronal-like cell model of PD, by overexpression of PGC-1α to detect evaluate the expression of proteases and molecular chaperones of involved in the mtUPR, as well as the expression of PGC-1α and LRPPRC, illustrated the distribution of LRPPRC. Remarkably, the mtUPR activation reached maximal at 24 h after MPP + treatment in SH-SY5Y cells, which the protein and transcription levels of the proteases and molecular chaperones reached maximal. The proteases and molecular chaperones were significantly increased when overexpressed PGC-1α, which indicated that PGC-1α overexpression activated the mtUPR, and PGC-1α had a protective effect on SH-SY5Y cells. The expression levels of PGC-1α and LRPPRC were significantly improved in the PGC-1α overexpression groups. LRPPRC was markedly reduced in the nucleus, suggesting that PGC-1α overexpression may play a protective role to the mitochondria through LRPPRC. Our finding indicates that overexpression of PGC-1α may activate mtUPR, reducing the oxidative stress injury induced by MPP + through LRPPRC signaling, thus maintain mitochondrial homeostasis.

Background The high incidence of cerebral apoplexy makes it one of the most important causes of adult disability. Gait disorder is one of the hallmark symptoms in the sequelae of cerebral apoplexy. The recovery of walking ability is critical for improving patients’ quality of life. Innovative virtual reality technology has been widely used in post-stroke rehabilitation, whose effectiveness and safety have been widely verified. To date, however, there are few studies evaluating the effect of immersive virtual reality on stroke-related gait rehabilitation. This study outlines the application of immersive VR-assisted rehabilitation for gait rehabilitation of stroke patients for comparative evaluation with traditional rehabilitation. Methods The study describes a prospective, randomized controlled clinical trial. Thirty-six stroke patients will be screened and enrolled as subjects within 1 month of initial stroke and randomized into two groups. The VRT group ( n  = 18) will receive VR-assisted training (30 min) 5 days/week for 3 weeks. The non-VRT group ( n  = 18) will receive functional gait rehabilitation training (30 min) 5 days/week for 3 weeks. The primary outcomes and secondary outcomes will be conducted before intervention, 3 weeks after intervention, and 6 months after intervention. The primary outcomes will include time “up & go” test (TUGT). The secondary outcomes will include MMT muscle strength grading standard (MMT), Fugal-Meyer scale (FMA), motor function assessment scale (MAS), improved Barthel index scale (ADL), step with maximum knee angle, total support time, step frequency, step length, pace, and stride length. Discussion Virtual reality is an innovative technology with broad applications, current and prospective. Immersive VR-assisted rehabilitation in patients with vivid treatment scenarios in the form of virtual games will stimulate patients’ interest through active participation. The feedback of VR games can also provide patients with performance awareness and effect feedback, which could be incentivizing. This study may reveal an improved method of stroke rehabilitation which can be helpful for clinical decision-making and future practice. Trial registration Chinese Clinical Trial Registry ChiCTR1900025375 . Registered on 25 August 2019

The effective management and therapies for Parkinson's disease (PD) require appropriate clinical evaluation. The Parkinson's KinetiGraph (PKG) is a wearable sensor system that can monitor the motion characteristics of PD objectively and continuously. This study was aimed to assess the correlations between PKG data and clinical scores of bradykinesia, rigidity, tremor, and fluctuation. It also aims to explore the application value of identifying early motor symptoms. An observational study of 100 PD patients wearing the PKG for ≥ 6 days was performed. It provides a series of data, such as the bradykinesia score (BKS), percent time tremor (PTT), dyskinesia score (DKS), and fluctuation and dyskinesia score (FDS). PKG data and UPDRS scores were analyzed, including UPDRS III total scores, UPDRS III-bradykinesia scores (UPDRS III-B: items 23-26, 31), UPDRS III-rigidity scores (UPDRS III-R: item 22), and scores from the Wearing-off Questionnaire (WOQ-9). This study shows that there was significant correlation between BKS and UPDRS III scores, including UPDRS III total scores, UPDRS III-B, and UPDRS III-R scores ( = 0.479-0.588, ≤ 0.001), especially in the early-stage group ( = 0.682, < 0.001). Furthermore, we found that BKS in patients with left-sided onset (33.57 ± 5.14, = 37) is more serious than in patients with right-sided onset (29.87 ± 6.86, = 26). Our findings support the feasibility of using the PKG to detect abnormal movements, especially bradykinesia in PD. It is suitable for the early detection, remote monitoring, and timely treatment of PD symptoms.

Mitochondria are essential organelles that perform important roles in cell biologies such as ATP synthesis, metabolic regulation, immunomodulatory, and apoptosis. Parkinson’s disease (PD) is connected with mitochondrial neuronal damage related to mitochondrial unfolded protein response (mtUPR). Rosmarinic acid (RA) is a naturally occurring hydroxylated polyphenolic chemical found in the Boraginaceae and the Labiatae subfamily Nepetoideae. This study looked into RA’s protective effect against mitochondrial loss in the substantia nigra (SN) caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the underlying mechanism associated with the mtUPR. Pretreatment with RA reduced motor impairments and dopaminergic neuronal degeneration in the SN of a mouse model injected with MPTP. Pretreatment of SH-SY5Y cells from cell viability loss, morphological damage, and oxidative stress. Furthermore, RA pre-injection suppressed MPTP-induced mtUPR, lowered the expression of HSPA9, HSPE1, CLPP, LONP1, and SIRT 4, and protected the MPTP-mice and SH-SY5Y cells from mitochondrial failure. These findings imply that RA can prevent Parkinson’s disease by preventing mitochondrial damage in dopaminergic neurons in Parkinson’s disease via alleviating mitochondrial unfolded protein response.

Parkinson's disease (PD), as a common neurodegenerative disease, currently has no effective therapeutic approaches to delay or stop its progression. There is an urgent need to further define its pathogenesis and develop new therapeutic targets. An increasing number of studies have shown that members of the sirtuin (SIRT) family are differentially involved in neurodegenerative diseases, indicating their potential to serve as targets in therapeutic strategies. Mitochondrial SIRT4 possesses multiple enzymatic activities, such as deacetylase, ADP ribosyltransferase, lipoamidase, and deacylase activities, and exhibits different enzymatic activities and target substrates in different tissues and cells; thus, mitochondrial SIRT4 plays an integral role in regulating metabolism. However, the role and mechanism of SIRT4 in PD are not fully understood. This study aimed to investigate the potential mechanism and possible regulatory targets of SIRT4 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. The expression of the SIRT4 protein in the MPTP-induced PD mouse mice or key familial Parkinson disease protein 7 knockout (DJ-1 KO) rat was compared against the control group by western blot assay. Afterwards, quantitative proteomics and bioinformatics analyses were performed to identify altered proteins in the vitro model and reveal the possible functional role of SIRT4. The most promising molecular target of SIRT4 were screened and validated by viral transfection, western blot assay and reverse transcription quantitative PCR (RT-qPCR) assays. The expression of the SIRT4 protein was found to be altered both in the MPTP-induced PD mouse mice and DJ-1KO rats. Following the viral transfection of SIRT4, a quantitative proteomics analysis identified 5,094 altered proteins in the vitro model, including 213 significantly upregulated proteins and 222 significantly downregulated proteins. The results from bioinformatics analyses indicated that SIRT4 mainly affected the ribosomal pathway, propionate metabolism pathway, peroxisome proliferator-activated receptor (PPAR) signaling pathway and peroxisome pathway in cells, and we screened 25 potential molecular targets. Finally, only fatty acid binding protein 4 (FABP4) in the PPAR signaling pathway was regulated by SIRT4 among the 25 molecules. Importantly, the alterations in FABP4 and PPARγ were verified in the MPTP-induced PD mouse model. Our results indicated that FABP4 in the PPAR signaling pathway is the most promising molecular target of SIRT4 in an MPTP-induced mouse model and revealed the possible functional role of SIRT4. This study provides a reference for future drug development and mechanism research with SIRT4 as a target or biomarker.

[This corrects the article DOI: 10.3389/fnins.2022.1035444.].

Background: Movement fluctuations are the main complication of Parkinson's disease (PD) patients receiving long-term levodopa (L-dopa) treatment. We compared and ranked the efficacy and safety of dopamine agonists (DAs) with regard to motor fluctuations by using a Bayesian network meta-analysis (NMA) to quantify information from randomized controlled trials (RCTs). Methods and Findings: We carried out a systematic review and meta-analysis, and only RCTs comparing DAs for advanced PD were included. Electronic databases (PubMed, Embase, and Cochrane Library) were systematically searched for relevant studies published until January 2021. Two reviewers independently extracted individual study data and evaluated studies for risk of bias using the Cochrane Risk of Bias tool. Network meta-analyses using a Bayesian framework were used to calculate the related parameters. The pre-specified primary and secondary outcomes were efficacy (“ON” time without troublesome dyskinesia, “OFF” time, “ON” time, “UPDRS-III,” and “UPDRS-II”) and safety [treatment-emergent adverse events (TEAE) and other adverse events] of DAs. The results are presented as the surface under the cumulative ranking (SUCRA) curve. A total of 20 RCTs assessing 6,560 patients were included. The general DA effects were ranked from high to low with respect to the amount of “ON” time without troublesome dyskinesia as follows: apomorphine (SUCRA = 97.08%), pramipexole_IR (probability = 79.00%), and ropinirole_PR (SUCRA = 63.92%). The general safety of DAs was ranked from high to low with respect to TEAE as follows: placebo (SUCRA = 74.49%), pramipexole_ER (SUCRA = 63.6%), sumanirole (SUCRA = 54.07%), and rotigotine (SUCRA = 53.84%). Conclusions: This network meta-analysis shows that apomorphine increased “ON” time without troublesome dyskinesia and decreased “OF” time for advanced PD patients. The addition of pramipexole, ropinirole, or rotigotine to levodopa treatment in advanced PD patients with motor fluctuations increased “ON” time without troublesome dyskinesia, improved the UPDRS III scores, and ultimately ameliorated the UPDRS II scores, thereby maximizing its benefit. This NMA of pramipexole, ropinirole, and rotigotine represents an effective treatment option and has an acceptable safety profile in patients with advanced PD.

To compare the efficacy of deep brain stimulation (DBS) and MRI-guided focused ultrasound (MRIgFUS) in parkinsonian tremor. We performed a network meta-analysis based on a Bayesian framework. We searched the literature for articles published between January 1990 and October 2020 using three databases: PubMed, Embase and Cochrane Library (The Cochrane Database of Systematic Reviews). A total of 24 studies were included in our analysis, comprising data from 784 participants. Our findings revealed similar efficacy of DBS and MRIgFUS in parkinsonian tremor suppression. Compared with internal globus pallidus (GPi)-MRIgFUS, GPi-DBS -1.84 (–6.44, 2.86), pedunculopontine nucleus (PPN)_DBS –3.28 (–9.28, 2.78), PPN and caudal zona incerta (cZI)-DBS 0.40 (–6.16, 6.87), subthalamic nucleus (STN)_DBS 0.89 (–3.48, 5.30), STN and cZI-DBS 1.99 (–4.74, 8.65), ventral intermediate nucleus(VIM)_DBS 1.75 (–2.87, 6.48), VIM_FUS 0.72 (–5.27, 6.43), cZI-DBS 0.27 (–4.75, 5.36) were no significantly difference. Compared with VIM-MRIgFUS, GPi-DBS -2.55(-6.94, 2.21), GPi-FUS -0.72 (–6.43, 5.27), PPN_DBS -4.01(–9.97, 2.11), PPN and cZI-DBS -0.32 (-6.73, 6.36), STN_DBS 0.16 (–3.98, 4.6), STN and cZI-DBS 1.31(-5.18,7.87), VIM-DBS 1.00(-3.41, 5.84)and cZI-DBS –0.43 (–5.07, 4.68) were no significantly difference. With respect to the results for the treatment of motor symptoms, GPi-DBS, GPi-MRIgFUS, STN-DBS and cZI-DBS were significantly more efficacious than baseline (GPi-DBS 15.24 (5.79, 24.82), GPi-MRIgFUS 13.46 (2.46, 25.10), STN-DBS 19.62 (12.19, 27.16), cZI-DBS 14.18 (1.73, 26.89). The results from the surface under the cumulative ranking results showed that STN-DBS ranked first, followed by combined PPN and cZI-DBS, and PPN-DBS ranked last. MRIgFUS, an efficacious intervention for improving parkinsonian tremor, has not demonstrated to be inferior to DBS in parkinsonian tremor suppression. Hence, clinicians should distinguish individual patients’ symptoms to ensure that the appropriate intervention and therapeutic approach are applied.

Introduction Prodromal Parkinson's disease (PD) carriers of dual leucine‐rich repeat kinase 2 (LRRK2) and glucosylceramidase β (GBA) variants are rare, and their biomarkers are less well developed. Objective This study aimed to investigate the biomarkers for diagnosing the prodromal phase of LRRK2‐GBA‐PD (LRRK2‐GBA‐prodromal). Methods We assessed the clinical and whole‐brain white matter microstructural characteristics of 54 prodromal PD carriers of dual LRRK2 (100% M239T) and GBA (95% N409S) variants, along with 76 healthy controls (HCs) from the Parkinson's Progression Markers Initiative (PPMI) cohort. Results By analyzing the four values of 100 nodes on 20 fiber bundles, totaling 8000 data points, we identified the smallest p value in the fractional anisotropy (FA) value of the 38th segment of left corticospinal tract (L‐CST) with differences between LRRK2‐GBA‐prodromal and HCs (p = 8.94 × 10−9). The FA value of the 38th node of the L‐CST was significantly lower in LRRK2‐GBA‐prodromal (FA value, 0.65) compared with HCs (FA value, 0.71). The receiver‐operating characteristic curve showed a cut‐off value of 0.218 for the FA value of L‐CST, providing sufficient sensitivity (79.2%) and specificity (72.2%) to distinguish double mutation prodromal PD from the healthy population. Conclusion L‐CST, especially the 38th node, may potentially serve as a biomarker for distinguishing individuals with double mutation prodromal PD from the healthy population. Identification of a specific biomarker, the 38th node of the left corticospinal tract (L‐CST), for distinguishing double mutation prodromal Parkinson's disease (LRRK2‐GBA‐prodromal) from healthy individuals. This finding has potential implications for early diagnosis and personalized medical management.