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Mitochondrion Jun 2024Mitochondria are singular cell organelles essential for many cellular functions, which includes responding to stress, regulating calcium levels, maintaining protein... (Review)
Review
Mitochondria are singular cell organelles essential for many cellular functions, which includes responding to stress, regulating calcium levels, maintaining protein homeostasis, and coordinating apoptosis response. The vitality of cells, therefore, hinges on the optimal functioning of these dynamic organelles. Mitochondrial Quality Control Mechanisms (MQCM) play a pivotal role in ensuring the integrity and functionality of mitochondria. Perturbations in these mechanisms have been closely associated with the pathogenesis of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Compelling evidence suggests that targeting specific pathways within the MQCM could potentially offer a therapeutic avenue for rescuing mitochondrial integrity and mitigating the progression of neurodegenerative diseases. The intricate interplay of cellular stress, protein misfolding, and impaired quality control mechanisms provides a nuanced understanding of the underlying pathology. Consequently, unravelling the specific MQCM dysregulation in neurodegenerative disorders becomes paramount for developing targeted therapeutic strategies. This review delves into the impaired MQCM pathways implicated in neurodegenerative disorders and explores emerging therapeutic interventions. By shedding light on pharmaceutical and genetic manipulations aimed at restoring MQCM efficiency, the discussion aims to provide insights into novel strategies for ameliorating the progression of neurodegenerative diseases. Understanding and addressing mitochondrial quality control mechanisms not only underscore their significance in cellular health but also offer a promising frontier for advancing therapeutic approaches in the realm of neurodegenerative disorders.
PubMed: 38944367
DOI: 10.1016/j.mito.2024.101926 -
Experimental Neurology Jun 2024Alleviation of motor impairment by aerobic exercise (AE) in Parkinson's disease (PD) patients points to activation of neurobiological mechanisms that may be targetable...
Moderate intensity aerobic exercise alleviates motor deficits in 6-OHDA lesioned rats and reduces serum levels of biomarkers of Parkinson's disease severity without recovery of striatal dopamine or tyrosine hydroxylase.
Alleviation of motor impairment by aerobic exercise (AE) in Parkinson's disease (PD) patients points to activation of neurobiological mechanisms that may be targetable by therapeutic approaches. However, evidence for AE-related recovery of striatal dopamine (DA) signaling or tyrosine hydroxylase (TH) loss has been inconsistent in rodent studies. This ambiguity may be related to the timing of AE intervention in relation to the status of nigrostriatal neuron loss. Here, we replicated human PD at diagnosis by establishing motor impairment with >80% striatal DA and TH loss prior to initiating AE, and assessed its potential to alleviate motor decline and restore DA and TH loss. We also evaluated if serum levels of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), biomarkers of human PD severity, changed in response to AE. 6-hydroxydopamine (6-OHDA) was infused unilaterally into rat medial forebrain bundle to induce progressive nigrostriatal neuron loss over 28 days. Moderate intensity AE (3× per week, 40 min/session), began 8-10 days post-lesion following establishment of impaired forelimb use. Striatal tissue DA, TH protein and mRNA, and serum levels of NfL/GFAP were determined 3-wks after AE began. Despite severe striatal DA depletion at AE initiation, forelimb use deficits and hypokinesia onset were alleviated by AE, without recovery of striatal DA or TH protein loss, but reduced NfL and GFAP serum levels. This proof-of-concept study shows AE alleviates motor impairment when initiated with >80% striatal DA loss without obligate recovery of striatal DA or TH protein. Moreover, the AE-related reduction of NfL and GFAP serum levels may serve as objective blood-based biomarkers of AE efficacy.
PubMed: 38944332
DOI: 10.1016/j.expneurol.2024.114875 -
Clinical Neurology and Neurosurgery Jun 2024Parkinson's disease (PD) is the second most prevalent neurodegenerative condition after Alzheimer's disease and it represents one of the fastest emerging neurological... (Review)
Review
Parkinson's disease (PD) is the second most prevalent neurodegenerative condition after Alzheimer's disease and it represents one of the fastest emerging neurological diseases worldwide. PD is usually diagnosed after the third decade of life with symptoms like tremors at rest and muscle stiffness. Rapid Eye Movement sleep behavioral disorder (RBD) is another disorder that is caused by a loss of typical muscle relaxation during sleep with a lot of motor activity. Usually, RBD is strongly associated with PD. Recent studies have demonstrated that PD reduces the life expectancy of patients to 10 and 20 years after being diagnosed. In addition, delayed diagnosis and treatment of these neurological disorders have significant socio-economic impacts on patients, their partners and on the general public. Often, it is not clear about PD associated financial burdens both in low and high-income countries. On the other hand, PD triggers neurological variations that affect differences in the dopamine transporter (DAT) and in glucose metabolism. Therefore, positron emission tomography (PET) using specific DAT radiotracers and fluorine-18 labeled desoxyglucose (FDG) has being considered a key imaging technique that could be applied clinically for the very early diagnosis of RBD and in PD. However, a few myths about PET is that it is very expensive. Here, we looked at the cost of treatment of PD and RBD in relation to early PET imaging. Our finding suggests that PET imaging might also be a cost sparing diagnostic option in the management of patients with PD and RBD, not only for first world countries as it is the case now but also for the third world countries. Therefore, PET is a cost-effective imaging technique for very early diagnostic of RBD and PD.
PubMed: 38944021
DOI: 10.1016/j.clineuro.2024.108404 -
Clinical Neurophysiology : Official... Jun 2024We aimed to establish specific biomarkers of Parkinson's disease (PD) by comparing activity of more affected (MA) and less affected (LA) subthalamic nucleus (STN) of...
OBJECTIVE
We aimed to establish specific biomarkers of Parkinson's disease (PD) by comparing activity of more affected (MA) and less affected (LA) subthalamic nucleus (STN) of patients with prominent clinical asymmetry.
METHODS
We recorded single unit activity and local field potentials (LFP) of the STN during deep brain stimulation surgeries. Neuronal firing patterns and discharge rate, as well as oscillatory features of both single cells and LFP, were analyzed.
RESULTS
We observed notable differences in proportions of irregular-burst and pause-burst, but not tonic neurons, between the hemispheres. Oscillations of pause-burst neurons correlated significantly with the bradykinesia and rigidity scores of the corresponding hemibody. LFP derived from MA STN featured greater power in 12-15 Hz.
CONCLUSIONS
Our results provide evidence that the increased proportion of units with prolonged pauses may be associated with PD. We also speculate that some of them may gain rhythmicity in the alpha-beta range in relation to hypokinetic symptoms, long-term disease, or both.
SIGNIFICANCE
Our findings highlight the relation between specific oscillatory features of the STN, predominance of subthalamic pause-burst units and PD pathophysiology.
PubMed: 38943791
DOI: 10.1016/j.clinph.2024.06.003 -
Parkinsonism & Related Disorders Jun 2024Alpha-synucleinopathies are prevalent neurological disorders that cause significant disability, leading to progressive clinical deterioration that is currently managed...
Alpha-synucleinopathies are prevalent neurological disorders that cause significant disability, leading to progressive clinical deterioration that is currently managed solely through symptomatic treatment. Efforts to evaluate disease-modifying therapies during the established stage of the disease have not yielded positive outcomes in terms of clinical or imaging efficacy endpoints. However, alpha-synucleinopathies have a long prodromal phase that presents a promising opportunity for intervention with disease-modifying therapies. The presence of polysomnography-confirmed REM sleep behavior disorder (RBD) is the most reliable risk factor for identifying individuals in the prodromal stage of alpha-synucleinopathy. This paper discusses the rationale behind targeting idiopathic/isolated RBD in disease-modifying trials and outlines possible study designs, including strategies for patient stratification, selection of biomarkers to assess disease progression and patient eligibility, as well as the identification of suitable endpoints. Additionally, the potential targets for disease-modifying treatment in alpha-synucleinopathies are summarized.
PubMed: 38943771
DOI: 10.1016/j.parkreldis.2024.107042 -
Stem Cell Research Jun 2024Recent studies reported that the mutation in the THAP11 gene (THAP11) could be responsible for the inborn vitamin deficiency known as cobalamin disorder, by affecting...
Recent studies reported that the mutation in the THAP11 gene (THAP11) could be responsible for the inborn vitamin deficiency known as cobalamin disorder, by affecting the expression of the enzyme MMACHC, key in the cobalamin metabolism. However, the specifics of the molecular mechanism are largely unknown. In here we generated genetically modified human pluripotent stem cell lines with THAP11 mutation, providing a new research tool for futher exploring the molecular mechanism. The established hPSC lines remain pluripotent, showing expression of OCT3/4, differentiation capacity to the three germ layers and displaying normal karyotype.
PubMed: 38943762
DOI: 10.1016/j.scr.2024.103483 -
Clinics (Sao Paulo, Brazil) Jun 2024
PubMed: 38943705
DOI: 10.1016/j.clinsp.2024.100425 -
NeuroRehabilitation 2024Parkinson's disease (PD) is a progressive neurodegenerative disorder diagnosed by motor symptoms of bradykinesia, in combination with tremor, rigidity, or postural... (Review)
Review
BACKGROUND
Parkinson's disease (PD) is a progressive neurodegenerative disorder diagnosed by motor symptoms of bradykinesia, in combination with tremor, rigidity, or postural instability. Many studies document the effects of exercise-based interventions, but the benefit of different exercise types remains unclear.
OBJECTIVE
To provide a commentary on the Cochrane Review by Ernst et al. on the effectiveness of different types of physical exercise regarding motor signs, Quality of Life (QoL), and the occurrence of adverse events.
METHODS
A systematic search was performed in CENTRAL, MEDLINE, Embase, and other databases. The search was performed also in trial registries, conference proceedings, and reference list of identified studies.
RESULTS
The review included 154 RCTs (with 7837 participants). The network meta-analyses (NMAs) on the severity of motor signs and QoL included data from 60 (2721 participants) and 48 (3029 participants) trials, respectively. The evidence from the NMA suggests that dance, gait/balance/functional training probably have a moderate beneficial effect on the severity of motor signs, and multi-domain training probably has a small beneficial effect on the severity of motor signs. Endurance, aqua-based, strength/resistance, and mind-body training might have a small beneficial effect on the severity of motor signs. In addition, aqua-based training probably has a large beneficial effect on QoL, and mind-body, gait/balance/functional, and multi-domain training and dance might have a small beneficial effect on QoL.
CONCLUSIONS
Current evidence supports the promotion of physical exercise among people with PD, identifying only small differences between exercises in influencing the severity of motor signs and QoL.
Topics: Humans; Parkinson Disease; Quality of Life; Exercise Therapy
PubMed: 38943407
DOI: 10.3233/NRE-246004 -
Journal of Parkinson's Disease Jun 2024
PubMed: 38943399
DOI: 10.3233/JPD-249006 -
Journal of Parkinson's Disease Jun 2024Natural health products have emerged as a potential symptomatic therapeutic approach for people with Parkinson's disease (PD).
BACKGROUND
Natural health products have emerged as a potential symptomatic therapeutic approach for people with Parkinson's disease (PD).
OBJECTIVE
To determine the prevalence of natural health product use, interest in natural health products, awareness of potential herb-drug interactions, and consultation of healthcare professionals regarding natural health products use among people with PD.
METHODS
Cross-sectional 4-item survey embedded in the PRIME-NL study, which is a population-based cohort of PD.
RESULTS
Of 367 people with PD, 36% reported having used natural health products to alleviate PD-related symptoms, with coffee, cannabis and turmeric being the most popular. Furthermore, 71% of people with PD were interested in learning more about natural health products. 39% of natural health products users were aware that these products could interact with PD medication and 39% had discussed their use with their healthcare professional.
CONCLUSIONS
Natural health products are commonly used to alleviate symptoms by people with PD, but most users are unaware that these products can interact with PD medication and do not discuss their consumption with their healthcare professional.
PubMed: 38943398
DOI: 10.3233/JPD-240102