Search Results (343)

S100 proteins, a family of Ca²⁺-binding proteins, play numerous roles in cellular processes such as proliferation, differentiation, and apoptosis. Recent evidence has highlighted their critical involvement in neuroinflammation, a pathological hallmark of various neurodegenerative disorders including Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease. Among these proteins, S100B and S100A8/A9 are particularly implicated in modulating inflammatory responses in the CNS. Acting as DAMPs, they interact with pattern recognition receptors like RAGE and TLRs, triggering pro-inflammatory signaling cascades and glial activation. While low concentrations of S100 proteins may support neuroprotective functions, increased levels are often associated with exacerbated inflammation and neuronal damage. This review explores the dualistic nature of S100 proteins in neuroinflammatory processes, their molecular interactions, and their potential as biomarkers and therapeutic targets in neurodegenerative disease management. Full article

Glucose is the main source of energy and the source of carbon for the biosynthesis of several molecules, such as neurotransmitters, for most mammalian cells. Therefore, the transport of glucose into cells is very important. There are described three distinct families of glucose transporters: facilitative glucose transporters (GLUTs), sodium-dependent glucose cotransporters (SGLTs), and a uniporter, the SWEET protein. Impaired function and/or expression of these transporters due to, for example, mutations in their genes, may cause severe diseases. Associations with the impaired function of glucose transporters have been described in the case of neurodegenerative diseases (NDs) such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, GLUT1-deficiency syndrome, stroke, and traumatic brain injury. Changes in the presence of glucose transporters may be a cause of NDs, and they may be the effect of NDs. On the other hand, in many cases of neurodegenerative diseases, changes in the expression of glucose transporters may be a targeted therapy in the treatment of patients with these diseases. Full article

Background and Objectives: Essential tremor (ET) is a common neurological disorder, typically presenting as bilateral, rhythmic, and symmetric kinetic or postural tremors. In contrast, Parkinson’s disease (PD) is a progressive neurodegenerative disorder, characterized by resting tremor, rigidity, bradykinesia, and postural instability. Although both disorders involve tremor, ET and PD differ in clinical presentation and pathophysiology: ET generally involves action tremor and has a strong familial component, while PD more commonly presents with resting tremor and a weaker family history. A subset of ET patients may develop Parkinsonian features over time, although the relationship between ET and subsequent PD remains unclear. Genetic studies have identified only a few pathogenic variants in ET, suggesting it develops as a result of multifactorial genetic and environmental influences rather than simple Mendelian inheritance. ET is also recognized as a risk factor for developing PD, although the underlying mechanisms remain poorly understood. This study aimed to clarify potential genetic overlaps and distinctions in patients diagnosed with both ET and PD. Materials and Methods: We retrospectively analyzed 40 patients with a family history of ET or PD who were initially diagnosed with ET and later developed PD. Genetic screening and clinical assessments were conducted to investigate associated variants and clinical features. Results: Among these 40 patients, 17 different mutations were detected in 16 individuals. Three pathogenic or likely pathogenic variants were identified. The clinical characteristics and treatment responses of these patients were reviewed in relation to their genetic findings. Notably, none of the identified variants had previously been reported in association with PD following ET. Conclusions: A comprehensive clinical and genetic evaluation of ET patients who develop PD may offer insights into the underlying pathophysiology and inform future therapeutic strategies. Our findings support the need for further studies to explore the genetic landscape of patients with overlapping ET and PD features. Full article

The family of voltage-dependent anion channels (VDACs) comprises three isoforms (VDAC-1, VDAC-2, VDAC-3). VDACs have been extensively described as localised in the outer mitochondrial membrane where they are involved in the exchange of ions, metabolites, and ATP/ADP between mitochondria and cytosol. The VDAC interacts with disease-specific proteins and thus regulates the mitochondrial function and controls the cellular energy resources, explaining its involvement in cell death and apoptosis. In addition, VDAC-1 and -2 can also be found at other cellular locations such as in the sarcoplasmic reticulum, in the endoplasmic reticulum, as well as in the plasma membrane. Through single-channel pore regulation, oligomerisation, or changed expression levels the VDAC is involved in different neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, Huntington’s disease, and others. Here, we critically summarise current discussions about the VDAC as a common key player for these diseases. We suggest that the VDAC acts as a transmembrane multifunctional regulatory protein which might serve as a pharmacological target for the development of novel drugs against neurodegenerative diseases such as the application of recombinant antibody technology. Full article

Carriers of Gaucher disease have an increased risk of developing Parkinson’s disease (PD). Identifying PD in its prodromal stage is crucial, as early detection before motor symptoms appear allows for potential interventions to salvage neurons and slow or prevent disease progression. At the Gaucher unit at Shaare Zedek Medical Center, we are following a large cohort of obligatory carriers of GBA1 variants (GBA1 carriers) and study ways to identify those at an increased risk for developing PD. In this study, we compared non-invasive prodromal PD tests in 164 GBA1 carriers and 49 participants with no genetic predisposition to PD (controls). The proportion of abnormal tests was compared between groups, and the risk factors for having abnormal tests (at least one or ≥20%) were studied. There were no differences between GBA1 carriers and controls in the frequency of abnormalities, having at least one abnormal test or having ≥20% abnormal tests. Having ≥20% of abnormal tests was associated mainly with age. Principal component analysis identified distinct cognitive, motor, and non-motor dysfunction patterns in GBA1 carriers compared to controls, with cognition in GBA1 carriers more closely linked to motor dysfunction and less influenced by mood and sleep, while in controls, executive function was tied to emotional state and fatigue. Younger carriers outperformed older ones in motor and some cognitive tasks. Those with a family history of PD showed worse cognitive scores than participants with no family history. Sex-based analysis revealed males obtained higher scores in most of the cognition subtests of the NeuroTrax test, whereas it was females in motor and other cognitive domains, mainly in the group of GBA1 carriers. A longitudinal follow-up of GBA1 carriers is ongoing to understand PD progression in GBA1 carriers with the aim of offering targeted intervention for those at higher risk. Full article

This paper draws on stories of receiving the diagnosis of Parkinson’s disease, which emerged from a broader narrative study exploring beliefs about exercise and challenges facing people with Parkinson’s disease. Background/Objectives: By interviewing people with Parkinson’s disease (PwPD) and their family members, this paper aimed to gain insights into PwPD’s experiences with diagnosis, its influence on exercise engagement, and access to services in Ireland. Methods: This study employed a qualitative research design, using purposeful and maximum variation sampling. PwPD (varying in age, sex, geographical setting, and disease severity) were recruited from urban physiotherapy services. Semi-structured interviews with 12 PwPD and a group interview with four family members were conducted between November 2022 and January 2023. The interviews were recorded, transcribed, and analysed using thematic analysis. Results: Four themes emerged: (1) firstly, there was disempowerment and emotional shock at diagnosis: PwPD expressed frustration with delays in diagnosis and with how language and empathy affected their ability to cope initially. (2) There was a lack of signposting and services access: a strong need exists for clear information on services and resources to prevent social disengagement. (3) In terms of exercise education and self-management support, PwPD lacked early exercise education and guidance, relying on self-education. (4) With regard to the emotional burden on family caregivers, family members manage care logistics and face emotional burdens, which they try to conceal. Conclusions: The delivery of a Parkinson’s diagnosis could be improved by recognising its psychosocial impact on PwPD and families. Providing clear information on services within weeks of diagnosis was considered crucial. Limited exercise education affected PwPD’s ability to self-manage. Early physiotherapy access is strongly recommended to help delay functional decline and encourage an active lifestyle. Full article

Familial Alzheimer’s disease (FAD) is a complex multifactorial disorder clinically characterized by cognitive impairment and memory loss. Pathologically, FAD is characterized by intracellular accumulation of the protein fragment Aβ42 (iAβ), hyperphosphorylated microtubule-associated protein TAU (p-TAU), and extensive degeneration of basal forebrain cholinergic neurons of the nucleus basalis of Meynert (NbM) and the medial septal nucleus (MSN), mainly caused by mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and PSEN2 gene. Since the dopaminergic system may contribute to FAD symptoms, alterations in the nigro-hippocampal pathway may be associated with cognitive impairment in FAD. Interestingly, p-α-synuclein (p-α-Syn), Aβ, and p-TAU have been found to coexist in vulnerable regions of postmortem AD brains. However, the mechanism by which Aβ, p-TAU, and α-Syn coexist in DAergic neurons in AD brains has not been determined. We generated PSEN1 I416T dopaminergic-like neurons (DALNs) from I416T menstrual stromal cells (MenSCs) in NeuroForsk 2.0 medium for 7 days and then cultured them in minimal culture medium (MCm) for another 4 days. On day 11, DALNs were analyzed for molecular and pathological markers by flow cytometry and fluorescence microscopy. We found that mutant DALNs showed increased accumulation of iAβ as well as increased phosphorylation of TAU at S202/T205 compared to WT DALNs. Thus, mutant DALNs exhibited typical pathological hallmarks of Alzheimer’s disease. Furthermore, PSEN1 I416T DALNs showed concomitant signs of OS as evidenced by the appearance of oxidized sensor protein DJ-1 (i.e., DJ-1C106-SO₃) and apoptotic markers TP53, pS63-c-JUN, PUMA, and cleavage caspase 3 (CC3). Notably, these DALNs exhibited PD-associated proteins such as intracellular accumulation of α-Syn (detected as aggregates of pS129-α-Syn) and phosphorylation of LRRK2 kinase at residue S935. In addition, mutant DALNs showed a 17.16- and 6.17-fold decrease in DA-induced Ca²⁺ flux, compared to WT DALNs. These observations suggest that iAβ and p-TAU, together with p-α-Syn, and p-LRRK2 kinase, may damage DAergic neurons and thereby contribute to the exacerbation of neuropathologic processes in FAD. Remarkably, the LRRK2 inhibitor PF-06447475 (PF-475) significantly reversed PSEN1 I416T-induced neuropathological markers in DAergic neurons. PF-465 inhibitor reduced iAβ, oxDJ-1C106-SO₃, and p-TAU. In addition, this inhibitor reduced pS935-LRRK2, pS129-αSYN, pS63-c-JUN, and CC3. We conclude that the observed neuroprotective effects of PF-475 are due to direct inhibition of LRRK2 activity and that the LRRK2 protein is upstream of the molecular cascade of apoptosis and proteinopathy. Our results suggest that PF-475 is an effective neuroprotective agent against endogenous PSEN1 I416T-induced neurotoxicity in DALNs coexisting with Parkinson’s disease markers. Therefore, PF-475 may be of great therapeutic value in FAD. Full article

Parkinson’s disease (PD) is a common movement disorder affecting adults. People diagnosed with PD can have a multitude of physical (motor) symptoms, including tremors, and rigidness, and psychological (non-motor) symptoms, including anxiety and depression. These symptoms dramatically affect daily living activities, including dressing oneself, preparing meals, and speaking and writing. Background/Objectives: To determine the symptom similarities and differences among PD patients, a method referred to as cluster analysis can be applied to patient data. This method can separate patients who differ by symptom presence while grouping patients with disease similarities. Previous PD cluster analysis studies provided patient groups that were defined by their age and disease duration—both numerical values—and excluded categorical values, such as patient gender, family history of the disease, and symptom presence. In addition, patient age and disease duration were limited in range in previous studies, providing a patient group that was too similar to divide into distinct clusters. Methods: This study utilized a decision tree cluster analysis method applied to categorical symptom data from PD patients. The applied cluster method automatically determines the number of clusters, reducing estimation errors, as many cluster analysis methods require the end user to estimate the number of clusters prior to applying cluster analysis. A post analysis of additional categorical and numerical variables was conducted, and this provided a means to describe the PD patient clusters in terms of gender, family history of PD, median age, disease duration, and symptom presence. The patient dataset utilized was accessed from the Parkinson’s Progression Markers Initiative (PPMI) website. Results and Conclusions: The cluster analysis results provided a means to describe seven PD patient subtypes based on motor symptom presence, with the largest PD patient cluster containing half of the patient sample, and these individuals had three of the motor symptoms present: bradykinesia, rigidity, and tremors. Full article

Background: Parkinson’s disease (PD) is a genetically complex neurodegenerative disorder. Up to 15% of cases are considered monogenic. However, research on monogenic PD has largely focused on populations of European ancestry, leaving gaps in our understanding of genetic variability in other populations. This study addresses this gap by analysing the allele frequencies of pathogenic and likely pathogenic variants in known monogenic PD genes across eight global populations, using data from the gnomAD database. Methods: We compiled a list of 27 genes associated with Mendelian PD from the Online Mendelian Inheritance in Man (OMIM) database, and identified pathogenic and likely pathogenic variants using ClinVar. We then performed pairwise comparisons of allele frequencies across populations included in the gnomAD database. Variants with significant frequency differences were further assessed using in silico pathogenicity predictions. Results: We identified 81 variants across 17 genes with statistically significant allele frequency differences between at least two populations. Variants in GBA1 were the most prevalent among monogenic PD-related genes, followed by PLA2G6, ATP13A2, VPS13C, and PRKN. GBA1 exhibited the greatest variability in allele frequencies, particularly the NM_000157.4:c.1226A>G (p.Asn409Ser) variant. Additionally, we observed significant population-specific differences in PD-related variants, such as the NM_032409.3:c.1040T>C (p.Leu347Pro) variant in PINK1, which was most prevalent in East Asian populations. Conclusions: Our findings reveal substantial population-specific differences in the allele frequencies of pathogenic variants linked to monogenic PD, emphasising the need for broader genetic studies beyond European populations. These insights have important implications for PD research, genetic screening, and understanding the pathogenesis of PD in diverse populations. Full article

Background/Objectives: The objective is to systematically review evidence from clinical and epidemiological studies for or against an association between essential tremor (ET) and Parkinson’s disease (PD). Methods: A literature search in PubMed (February 2025) used several combinations of keywords. Thirty-three studies (1960–2023) were identified. Results: The best available data are derived from a population-based study in Spain, followed by a cohort study in the US. Each of these prospective studies provided evidence that ET is a risk factor for PD, with elevated risks of ~4–5. In cross-sectional studies, in which the proportion of PD cases with ET has been reported, the weight of evidence demonstrates an association between ET and PD. In 16 (88.9%) of 18 family studies, the odds ratios or hazards ratios are elevated—i.e., there is considerable evidence that ET is over-represented in PD families and, conversely, PD is over-represented in ET families. Conclusions: A comprehensive review of published data strongly supports an association between ET and PD and, more specifically, provides evidence that ET is a risk factor for PD. Seven of nine review articles (and six of seven non-commissioned review articles) have concluded that there is an association between these two degenerative diseases. The “controversy” that surrounds the ET–PD association is more of a repeated myth than a well-informed reality. As a field, it would be more productive to finally move beyond uniformed debate and focus our efforts on attempts to elucidate the basis for the association to which the data are repeatedly pointing. Full article

Voltage-gated Ca²⁺ (Ca_V) channels are transmembrane proteins comprising the pore-forming subunit Ca_Vα₁ and the ancillary proteins Ca_Vα₂δ and Ca_Vβ. They are expressed in various tissues, including the nervous system, where they regulate Ca²⁺ entry in response to membrane potential changes. The increase in intracellular Ca²⁺ allows for regulating cell excitability and releasing neurotransmitters, among other cellular events. Leucine-rich repeat kinase 2 (LRRK2) is a serine–threonine kinase involved in vesicular mobilization. Previously, it has been shown that LRRK2 regulates neurotransmission by phosphorylating the Ca_Vβ auxiliary subunit of the Ca_V2.1 (P/Q-type) presynaptic channels. However, it is unknown whether the kinase can regulate the activity of other Ca_V channel subtypes, such as Ca_V1.3 (L-type), which play a significant role in the excitability of dopaminergic neurons in the substantia nigra pars compacta (SNc) and whose dysregulation contributes to neurodegeneration in Parkinson’s disease (PD). Here, we found potential phosphorylation sites for LRRK2 in Ca_Vβ₃ and examined how these molecules interact. We used immunoprecipitation and electrophysiology in HEK-293 cells expressing recombinant Ca_V1.3 channels, both with and without wild-type LRRK2 or its LRRK2^G2019S mutation, which plays a role in familial PD through a possible gain-of-toxic-function mechanism. Our results show that LRRK2^G2019S significantly increases current density through Ca_V1.3 channels, and this effect depends on the presence of Ca_Vβ₃. Site-directed mutagenesis revealed that phosphorylation at S152 in the sequence of Ca_Vβ₃ is necessary and sufficient to explain the abnormal regulation of the channels mediated by LRRK2^G2019S. These data provide new insights into the molecular regulation that mutant LRRK2 may exert on L-type Ca_V1.3 channels, which determine pacemaker activity in dopaminergic neurons of the SNc and may, therefore, play a relevant role in the molecular pathophysiology of PD. Full article

Sepiapterin Reductase Deficiency (SRD) is a rare inherited neurometabolic disorder caused by variants in the SPR gene, which may lead to developmental delays, psychomotor retardation, and cognitive impairments. Two consanguineous North African and Middle Eastern families are reported with multiple affected individuals presenting with developmental delay, ataxia, hypotonia, fatigue, and ptosis, or parkinsonism and cognitive impairment. Exome sequencing revealed a novel homozygous SPR c.560A>G (p.Glu187Gly) mutation that segregates with disease. According to molecular dynamics analysis, the substitution is predicted to compromise structural integrity, likely affecting ligand binding and catalytic activity. Elevated cerebrospinal fluid sepiapterin and biopterin levels, along with low neurotransmitter levels, were concordant with a genetic diagnosis of SRD and the reclassification of this variant as pathogenic. SRD patients manifest a broad constellation of symptoms, albeit well-managed using low-dose L-dopa/carbidopa. This study highlights the value of genetic testing in expediting early diagnosis and intervention to mitigate the onset of this disorder. Full article

Interferon Regulatory Factors (IRFs) are critical modulators of immune and inflammatory responses, yet their roles in Alzheimer’s disease (AD) and other neurodegenerative disorders remain incompletely understood. While IRFs are recognized for their regulatory functions in neuroinflammation, microglial activation, and neuronal survival, their dual roles as both drivers of pathological inflammation and mediators of neuroprotective pathways underscore a sophisticated regulatory paradox in neurodegenerative disorders. This review aims to synthesize current evidence on IRF-mediated neuroinflammation in AD and related diseases, focusing on the multifaceted functions of key IRF family members, including IRF1, IRF3, and IRF7. We critically evaluate their divergent roles: IRF1 and IRF3, for instance, exacerbate neuroinflammatory cascades and amyloid-beta (Aβ) pathology in AD, whereas IRF7 may paradoxically suppress inflammation under specific conditions. Additionally, we explore IRF dysregulation in Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington’s disease, emphasizing shared and distinct mechanisms across neurodegenerative disorders. Restoring IRF balance through genetic manipulation, small-molecule inhibitors, or microbiome-derived modulators could attenuate neuroinflammation, enhance Aβ clearance, and protect neuronal integrity. Ultimately, this work provides a framework for future research to harness IRF signaling pathways in the development of precision therapies for AD and other neurodegenerative diseases. Full article

Peak1-related, kinase-activating pseudokinase 1 (PRAG1), a member of the pseudopodium-enriched atypical kinase (PEAK) family of pseudokinases, has been reported to play a role in regulating cell morphology. However, the molecular mechanism for this function remains elusive. In this study, we demonstrate that PRAG1 forms dynamic condensates in cells mediated by its αN and αJ helices. Importantly, we found that PRAG1 condensates functioned in mediating cell contraction, while condensate-formation-deficient PRAG1 mutants lost this function. Remarkably, the formation of spherical PRAG1 condensates appears to be a common phenomenon in diverse stress models, as well as in dopaminergic (DA) neurons derived from a Parkinson’s disease patient. Our findings reveal a novel mechanism through which PRAG1 drives cell contraction and suggest a potential link between aberrant PRAG1 phase separation and stress-induced cell contraction. PRAG1 condensation drives cell contraction under stress. Full article

The ubiquitin-protein ligase E3A (UBE3A, aka E6-AP), an E3 ligase belonging to the HECT family, plays crucial roles in the stability of various proteins through the proteasomal degradation system. Abnormal UBE3A activity is essential for the initiation and progression of several cancers. A gain of function and an overdosage of maternal UBE3A is associated with an increased risk of autism spectrum disorders. Conversely, a loss of function due to mutations, deletions, paternal duplications, or imprinting defects in neurons leads to Angelman syndrome. Emerging evidence suggests that abnormal UBE3A activity may also contribute to the development of various brain disorders, including schizophrenia, Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease, making UBE3A a protein of significant interest. However, research on UBE3A’s functions in the brain has primarily focused on neurons due to the imprinting of UBE3A in mature neuronal cells, while being obscured in glia. This review outlines the expression of UBE3A in neurons and glial cells based on published studies, highlights newly identified patterns of UBE3A, such as its secretion, and emphasizes the involvement of UBE3A in neurodegenerative diseases. Furthermore, we summarize glial UBE3A and propose a model of bi-directional interactions between the neurons and glia mediated by UBE3A that underlies brain functions. Insights gained from this research could provide new avenues for therapeutic interventions targeting various brain disorders. Full article