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International Journal of Molecular... Jun 2024Parkinson's disease (PD) is a disease of an unknown origin. Despite that, decades of research have provided considerable evidence that alpha-synuclein (αSyn) is central... (Review)
Review
Parkinson's disease (PD) is a disease of an unknown origin. Despite that, decades of research have provided considerable evidence that alpha-synuclein (αSyn) is central to the pathogenesis of disease. Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are functional domains formed at contact sites between the ER and mitochondria, with a well-established function of MAMs being the control of lipid homeostasis within the cell. Additionally, there are numerous proteins localized or enriched at MAMs that have regulatory roles in several different molecular signaling pathways required for cellular homeostasis, such as autophagy and neuroinflammation. Alterations in several of these signaling pathways that are functionally associated with MAMs are found in PD. Taken together with studies that find αSyn localized at MAMs, this has implicated MAM (dys)function as a converging domain relevant to PD. This review will highlight the many functions of MAMs and provide an overview of the literature that finds αSyn, in addition to several other PD-related proteins, localized there. This review will also detail the direct interaction of αSyn and αSyn-interacting partners with specific MAM-resident proteins. In addition, recent studies exploring new methods to investigate MAMs will be discussed, along with some of the controversies regarding αSyn, including its several conformations and subcellular localizations. The goal of this review is to highlight and provide insight on a domain that is incompletely understood and, from a PD perspective, highlight those complex interactions that may hold the key to understanding the pathomechanisms underlying PD, which may lead to the targeted development of new therapeutic strategies.
Topics: Parkinson Disease; Humans; alpha-Synuclein; Endoplasmic Reticulum; Mitochondria; Animals; Signal Transduction; Autophagy
PubMed: 38928232
DOI: 10.3390/ijms25126525 -
International Journal of Molecular... Jun 2024Copper is a transition metal essential for growth and development and indispensable for eukaryotic life. This metal is essential to neuronal function: its deficiency, as... (Review)
Review
Copper is a transition metal essential for growth and development and indispensable for eukaryotic life. This metal is essential to neuronal function: its deficiency, as well as its overload have been associated with multiple neurodegenerative disorders such as Alzheimer's disease and Wilson's disease and psychiatric conditions such as schizophrenia, bipolar disorder, and major depressive disorders. Copper plays a fundamental role in the development and function of the human Central Nervous System (CNS), being a cofactor of multiple enzymes that play a key role in physiology during development. In this context, we thought it would be timely to summarize data on alterations in the metabolism of copper at the CNS level that might influence the development of neuropsychiatric symptoms. We present a non-systematic review with the study selection based on the authors' judgement to offer the reader a perspective on the most significant elements of neuropsychiatric symptoms in Wilson's disease. We highlight that Wilson's disease is characterized by marked heterogeneity in clinical presentation among patients with the same mutation. This should motivate more research efforts to disentangle the role of environmental factors in modulating the expression of genetic predisposition to this disorder.
Topics: Humans; Copper; Hepatolenticular Degeneration; Mental Disorders; Animals
PubMed: 38928192
DOI: 10.3390/ijms25126487 -
Genes Jun 2024Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG expansion on the huntingtin () gene and is characterized by progressive... (Review)
Review
Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG expansion on the huntingtin () gene and is characterized by progressive motor, cognitive, and neuropsychiatric decline. Recently, new genetic factors besides CAG repeats have been implicated in the disease pathogenesis. Most genetic modifiers are involved in DNA repair pathways and, as the cause of the loss of CAA interruption in the gene, they exert their main influence through somatic expansion. However, this mechanism might not be the only driver of HD pathogenesis, and future studies are warranted in this field. The aim of the present review is to dissect the many faces of genetics in HD pathogenesis, from cis- and trans-acting genetic modifiers to RNA toxicity, mitochondrial DNA mutations, and epigenetics factors. Exploring genetic modifiers of HD onset and progression appears crucial to elucidate not only disease pathogenesis, but also to improve disease prediction and prevention, develop biomarkers of disease progression and response to therapies, and recognize new therapeutic opportunities. Since the same genetic mechanisms are also described in other repeat expansion diseases, their implications might encompass the whole spectrum of these disorders.
Topics: Huntington Disease; Humans; Huntingtin Protein; Trinucleotide Repeat Expansion; Animals; Epigenesis, Genetic; DNA, Mitochondrial
PubMed: 38927742
DOI: 10.3390/genes15060807 -
Biology May 2024The literature offers a consensus on the association between exercise training (ET) protocols based on the adequate parameters of intensity and frequency, and several... (Review)
Review
The literature offers a consensus on the association between exercise training (ET) protocols based on the adequate parameters of intensity and frequency, and several adaptive alterations in the liver. Indeed, regular ET can reverse glucose and lipid metabolism disorders, especially from aerobic modalities, which can decrease intrahepatic fat formation. In terms of molecular mechanisms, the regulation of hepatic fat formation would be directly related to the modulation of the mechanistic target of rapamycin (mTOR), which would be stimulated by insulin signaling and Akt activation, from the following three different primary signaling pathways: (I) growth factor, (II) energy/ATP-sensitive, and (III) amino acid-sensitive signaling pathways, respectively. Hyperactivation of the Akt/mTORC1 pathway induces lipogenesis by regulating the action of sterol regulatory element binding protein-1 (SREBP-1). Exercise training interventions have been associated with multiple metabolic and tissue benefits. However, it is worth highlighting that the mTOR signaling in the liver in response to exercise interventions remains unclear. Hepatic adaptive alterations seem to be most outstanding when sustained by chronic interventions or high-intensity exercise protocols.
PubMed: 38927242
DOI: 10.3390/biology13060362 -
Biomolecules Jun 2024One of the biggest problems in the treatment of idiopathic Parkinson's disease is the lack of new drugs that slow its progression. L-Dopa remains the star drug in the... (Review)
Review
One of the biggest problems in the treatment of idiopathic Parkinson's disease is the lack of new drugs that slow its progression. L-Dopa remains the star drug in the treatment of this disease, although it induces severe side effects. The failure of clinical studies with new drugs depends on the use of preclinical models based on neurotoxins that do not represent what happens in the disease since they induce rapid and expansive neurodegeneration. We have recently proposed a single-neuron degeneration model for idiopathic Parkinson's disease that requires years to accumulate enough lost neurons for the onset of motor symptoms. This single-neuron degeneration model is based on the excessive formation of aminochrome during neuromelanin synthesis that surpass the neuroprotective action of the enzymes DT-diaphorase and glutathione transferase M2-2, which prevent the neurotoxic effects of aminochrome. Although the neurotoxic effects of aminochrome do not have an expansive effect, a stereotaxic injection of this endogenous neurotoxin cannot be used to generate a preclinical model in an animal. Therefore, the aim of this review is to evaluate the strategies for pharmacologically increasing the expression of DT diaphorase and GSTM2-2 and molecules that induce the expression of vesicular monoamine transporter 2, such as pramipexole.
Topics: Humans; Parkinson Disease; Animals; Neurons; Nerve Degeneration; Glutathione Transferase; Neuroprotective Agents; Disease Models, Animal; Antiparkinson Agents
PubMed: 38927076
DOI: 10.3390/biom14060673 -
Biomolecules May 2024The primary nucleation process of α-synuclein (AS) that forms toxic oligomeric species is the early stage of the pathological cause of Parkinson's disease. It is...
The primary nucleation process of α-synuclein (AS) that forms toxic oligomeric species is the early stage of the pathological cause of Parkinson's disease. It is well-known that copper influences this primary nucleation process. While significant efforts have been made to solve the structures of polymorphic AS fibrils, the structures of AS oligomers and the copper-bound AS oligomers at the molecular level and the effect of copper concentrations on the primary nucleation are elusive. Here, we propose and demonstrate new molecular mechanism pathways of primary nucleation of AS that are tuned by distinct copper concentrations and by a specific copper-binding site. We present the polymorphic AS dimers bound to different copper-binding sites at the atomic resolution in high- and low-copper concentrations, using extensive molecular dynamics simulations. Our results show the complexity of the primary nucleation pathways that rely on the copper concentrations and the copper binding site. From a broader perspective, our study proposes a new strategy to control the primary nucleation of other toxic amyloid oligomers in other neurodegenerative diseases.
Topics: alpha-Synuclein; Copper; Binding Sites; Molecular Dynamics Simulation; Humans; Protein Multimerization; Protein Binding; Parkinson Disease
PubMed: 38927031
DOI: 10.3390/biom14060627 -
Journal of Neuroengineering and... Jun 2024People with Parkinson's Disease (PD) show abnormal gait patterns compromising their independence and quality of life. Among all gait alterations due to PD, reduced step...
INTRODUCTION
People with Parkinson's Disease (PD) show abnormal gait patterns compromising their independence and quality of life. Among all gait alterations due to PD, reduced step length, increased cadence, and decreased ground-reaction force during the loading response and push-off phases are the most common. Wearable biofeedback technologies offer the possibility to provide correlated single or multi-modal stimuli associated with specific gait events or gait performance, hence promoting subjects' awareness of their gait disturbances. Moreover, the portability and applicability in clinical and home settings for gait rehabilitation increase the efficiency in the management of PD. The Wearable Vibrotactile Bidirectional Interface (BI) is a biofeedback device designed to extract gait features in real-time and deliver a customized vibrotactile stimulus at the waist of PD subjects synchronously with specific gait phases. The aims of this study were to measure the effect of the BI on gait parameters usually compromised by the typical bradykinetic gait and to assess its usability and safety in clinical practice.
METHODS
In this case series, seven subjects (age: 70.4 ± 8.1 years; H&Y: 2.7 ± 0.3) used the BI and performed a test on a 10-meter walkway (10mWT) and a two-minute walk test (2MWT) as pre-training (Pre-trn) and post-training (Post-trn) assessments. Gait tests were executed in random order with (Bf) and without (No-Bf) the activation of the biofeedback stimulus. All subjects performed three training sessions of 40 min to familiarize themselves with the BI during walking activities. A descriptive analysis of gait parameters (i.e., gait speed, step length, cadence, walking distance, double-support phase) was carried out. The 2-sided Wilcoxon sign-test was used to assess differences between Bf and No-Bf assessments (p < 0.05).
RESULTS
After training subjects improved gait speed (Pre-trn_No-Bf: 0.72(0.59,0.72) m/sec; Post-trn_Bf: 0.95(0.69,0.98) m/sec; p = 0.043) and step length (Pre-trn_No-Bf: 0.87(0.81,0.96) meters; Post-trn_Bf: 1.05(0.96,1.14) meters; p = 0.023) using the biofeedback during the 10mWT. Similarly, subjects' walking distance improved (Pre-trn_No-Bf: 97.5 (80.3,110.8) meters; Post-trn_Bf: 118.5(99.3,129.3) meters; p = 0.028) and the duration of the double-support phase decreased (Pre-trn_No-Bf: 29.7(26.8,31.7) %; Post-trn_Bf: 27.2(24.6,28.7) %; p = 0.018) during the 2MWT. An immediate effect of the BI was detected in cadence (Pre-trn_No-Bf: 108(103.8,116.7) step/min; Pre-trn_Bf: 101.4(96.3,111.4) step/min; p = 0.028) at Pre-trn, and in walking distance at Post-trn (Post-trn_No-Bf: 112.5(97.5,124.5) meters; Post-trn_Bf: 118.5(99.3,129.3) meters; p = 0.043). SUS scores were 77.5 in five subjects and 80.3 in two subjects. In terms of safety, all subjects completed the protocol without any adverse events.
CONCLUSION
The BI seems to be usable and safe for PD users. Temporal gait parameters have been measured during clinical walking tests providing detailed outcomes. A short period of training with the BI suggests improvements in the gait patterns of people with PD. This research serves as preliminary support for future integration of the BI as an instrument for clinical assessment and rehabilitation in people with PD, both in hospital and remote environments.
TRIAL REGISTRATION
The study protocol was registered (DGDMF.VI/P/I.5.i.m.2/2019/1297) and approved by the General Directorate of Medical Devices and Pharmaceutical Service of the Italian Ministry of Health and by the ethics committee of the Lombardy region (Milan, Italy).
Topics: Humans; Parkinson Disease; Aged; Male; Wearable Electronic Devices; Biofeedback, Psychology; Female; Gait Disorders, Neurologic; Middle Aged; Gait
PubMed: 38926876
DOI: 10.1186/s12984-024-01403-z -
BMC Surgery Jun 2024Lumbar degenerative conditions are a major cause of back pain and disability in individuals aged 45 and above. Gait analysis utilizes sensor technology to collect...
BACKGROUND
Lumbar degenerative conditions are a major cause of back pain and disability in individuals aged 45 and above. Gait analysis utilizes sensor technology to collect movement data, aiding in the evaluation of various gait aspects like spatiotemporal parameters, joint angles, neuromuscular activity, and joint forces. It is widely used in conditions such as cerebral palsy and knee osteoarthritis. This research aims to assess the effectiveness of 3D gait analysis in evaluating surgical outcomes and postoperative rehabilitation for lumbar degenerative disorders.
METHODS
A prospective self-controlled before-after study (n = 85) carried out at our Hospital (Sep 2018 - Dec 2021) utilized a 3D motion analysis system to analyze gait in patients with lumbar degenerative diseases. The study focused on the multifidus muscle, a crucial spinal muscle, during a minimally invasive lumbar interbody fusion surgery conducted by Shandong Weigao Pharmaceutical Co., Ltd. Pre- and postoperative assessments included time-distance parameters (gait speed, stride frequency, stride length, stance phase), hip flexion angle, and stride angle. Changes in 3D gait parameters post-surgery and during rehabilitation were examined. Pearson correlation coefficient was employed to assess relationships with the visual analog pain scale (VAS), Oswestry Disability Index (ODI), and Japanese Orthopedic Association (JOA) scores. Patient sagittal alignment was evaluated using "Surgimap" software from two types of lateral radiographs to obtain parameters like pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), lumbar lordosis (LL), intervertebral space height (DH), posterior height of the intervertebral space (PDH) at the operative segment, and anterior height of the intervertebral space (ADH).
RESULTS
By the 6th week post-operation, significant improvements were observed in the VAS score, JOA score, and ODI score of the patients compared to preoperative values (P < 0.05), along with notable enhancements in 3D gait quantification parameters (P < 0.05). Pearson correlation analysis revealed a significant positive correlation between improvements in 3D gait quantification parameters and VAS score, JOA score, and ODI value (all P < 0.001).
CONCLUSION
3D gait analysis is a valuable tool for evaluating the efficacy of surgery and rehabilitation training in patients.
Topics: Humans; Male; Gait Analysis; Female; Middle Aged; Prospective Studies; Lumbar Vertebrae; Spinal Fusion; Aged; Treatment Outcome; Imaging, Three-Dimensional; Intervertebral Disc Degeneration; Pain Measurement; Disability Evaluation
PubMed: 38926745
DOI: 10.1186/s12893-024-02486-0 -
Scientific Reports Jun 2024Visual hallucinations in Lewy body disease (LBD) can be differentiated based on phenomenology into minor phenomena (MVH) and complex hallucinations (CVH). MVH include a...
Visual hallucinations in Lewy body disease (LBD) can be differentiated based on phenomenology into minor phenomena (MVH) and complex hallucinations (CVH). MVH include a variety of phenomena, such as illusions, presence and passage hallucinations occurring at early stages of LBD. The neural mechanisms of visual hallucinations are largely unknown. The hodotopic model posits that the hallucination state is due to abnormal activity in specialized visual areas, that occurs in the context of wider network connectivity alterations and that phenomenology of VH, including content and temporal characteristics, may help identify brain regions underpinning these phenomena. Here we investigated both the topological and hodological neural basis of visual hallucinations integrating grey and white matter imaging analyses. We studied LBD patients with VH and age matched healthy controls (HC). VH were assessed using a North-East-Visual-Hallucinations-Interview that captures phenomenological detail. Then we applied voxel-based morphometry and tract based spatial statistics approaches to identify grey and white matter changes. First, we compared LBD patients and HC. We found a reduced grey matter volume and a widespread damage of white tracts in LBD compared to HC. Then we tested the association between CVH and MVH and grey and white matter indices. We found that CVH duration was associated with decreased grey matter volume in the fusiform gyrus suggesting that LBD neurodegeneration-related abnormal activity in this area is responsible for CVH. An unexpected finding was that MVH severity was associated with a greater integrity of white matter tracts, specifically those connecting dorsal, ventral attention networks and visual areas. Our results suggest that networks underlying MVH need to be partly intact and functional for MVH experiences to occur, while CVH occur when cortical areas are damaged. The findings support the hodotopic view and the hypothesis that MVH and CVH relate to different neural mechanisms, with wider implications for the treatment of these symptoms in a clinical context.
Topics: Humans; Hallucinations; Lewy Body Disease; Gray Matter; Female; White Matter; Male; Aged; Magnetic Resonance Imaging; Aged, 80 and over; Case-Control Studies; Middle Aged
PubMed: 38926597
DOI: 10.1038/s41598-024-65536-w -
Pediatric Research Jun 2024Cerebral palsy (CP) is the core neurodevelopmental disorder affecting movement. Several distinct movement disorders can occur in people with cerebral palsy. Dystonia is...
Cerebral palsy (CP) is the core neurodevelopmental disorder affecting movement. Several distinct movement disorders can occur in people with cerebral palsy. Dystonia is a movement disorder that causes non-velocity-dependent hypertonia and/or abnormal, often repetitive, twisting movements, and/or postures. Dystonia occurs more frequently in patients with CP than has been recognized previously, and is treated differently than other aspects of CP. Dystonia is an important cause of chronic pain, hospitalization, and musculoskeletal complications. We describe recent advances in dystonia diagnosis in patients with cerebral palsy and highlight focus areas for ongoing research and clinical care. IMPACT: Dystonia is a movement disorder that is more common in people with cerebral palsy (CP) than previously thought. Dystonia contributes to hospitalization, chronic pain, and complications in CP patients. People with dystonic CP require different tools to diagnose and treat their condition. We summarize current state of the art in dystonia in CP and identify areas of focus for future work.
PubMed: 38926549
DOI: 10.1038/s41390-024-03327-9