Browsing by Subject "Alpha-synuclein"
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Item Alpha-synuclein (SNCA) polymorphisms exert protective effects on memory after mild traumatic brain injury(Elsevier, 2016-09-06) Shee, Kevin; Lucas, Alexandra; Flashman, Laura A.; Nho, Kwangsik; Tsongalis, Gregory J.; McDonald, Brenna C.; Saykin, Andrew J.; McAllister, Thomas W.; Rhodes, C. Harker; Psychiatry, School of MedicineProblems with attention and short-term learning and memory are commonly reported after mild traumatic brain injury (mTBI). Due to the known relationships between α-synuclein (SNCA), dopaminergic transmission, and neurologic deficits, we hypothesized that SNCA polymorphisms might be associated with cognitive outcome after mTBI. A cohort of 91 mTBI patients one month after injury and 86 healthy controls completed a series of cognitive tests assessing baseline intellectual function, attentional function, and memory, and was genotyped at 13 common single nucleotide polymorphisms (SNPs) in the SNCA gene. Significant differences in two memory measures (p = 0.001 and 0.002), but not baseline intellectual function or attentional function tasks, were found between the mTBI group and controls. A highly significant protective association between memory performance and SNCA promoter SNP rs1372525 was observed in the mTBI patients (p = 0.006 and 0.029 for the long and short delay conditions of the California Verbal Learning Tests, respectively), where the presence of at least one copy of the A (minor) allele was protective after mTBI. These results may help elucidate the pathophysiology of cognitive alterations after mTBI, and thus warrant further investigation.Item The alpha-synuclein 5'untranslated region targeted translation blockers: anti-alpha synuclein efficacy of cardiac glycosides and Posiphen(Springer Nature, 2011-03) Rogers, Jack T.; Mikkilineni, Sohan; Castelvetri, Ippolita Cantuti; Smith, Deborah H.; Huang, Xudong; Bandyopadhyay, Sanghamitra; Cahill, Catherine M.; Maccecchini, Maria L.; Lahiri, Debomoy K.; Greig, Nigel H.; Psychiatry, School of MedicineIncreased brain α-synuclein (SNCA) protein expression resulting from gene duplication and triplication can cause a familial form of Parkinson's disease (PD). Dopaminergic neurons exhibit elevated iron levels that can accelerate toxic SNCA fibril formation. Examinations of human post mortem brain have shown that while mRNA levels for SNCA in PD have been shown to be either unchanged or decreased with respect to healthy controls, higher levels of insoluble protein occurs during PD progression. We show evidence that SNCA can be regulated via the 5'untranslated region (5'UTR) of its transcript, which we modeled to fold into a unique RNA stem loop with a CAGUGN apical loop similar to that encoded in the canonical iron-responsive element (IRE) of L- and H-ferritin mRNAs. The SNCA IRE-like stem loop spans the two exons that encode its 5'UTR, whereas, by contrast, the H-ferritin 5'UTR is encoded by a single first exon. We screened a library of 720 natural products (NPs) for their capacity to inhibit SNCA 5'UTR driven luciferase expression. This screen identified several classes of NPs, including the plant cardiac glycosides, mycophenolic acid (an immunosuppressant and Fe chelator), and, additionally, posiphen was identified to repress SNCA 5'UTR conferred translation. Western blotting confirmed that Posiphen and the cardiac glycoside, strophanthidine, selectively blocked SNCA expression (~1 μM IC(50)) in neural cells. For Posiphen this inhibition was accelerated in the presence of iron, thus providing a known APP-directed lead with potential for use as a SNCA blocker for PD therapy. These are candidate drugs with the potential to limit toxic SNCA expression in the brains of PD patients and animal models in vivo.Item Comorbidities in Early-Onset Sporadic versus Presenilin-1 Mutation-Associated Alzheimer’s Disease Dementia: Evidence for Dependency on Alzheimer’s Disease Neuropathological Changes(medRxiv, 2023-08-16) Sepulveda-Falla, Diego; Lanau, Carlos Andrés Villegas; White, Charles, III; Serrano, Geidy E.; Acosta-Uribe, Juliana; Mejía-Cupajita, Barbara; Villalba-Moreno, Nelson David; Lu, Pinzhang; Glatzel, Markus; Kofler, Julia K.; Ghetti, Bernardino; Frosch, Matthew P.; Restrepo, Francisco Lopera; Kosik, Kenneth S.; Beach, Thomas G.; Pathology and Laboratory Medicine, School of MedicineAutopsy studies have demonstrated that comorbid neurodegenerative and cerebrovascular disease occur in the great majority of subjects with Alzheimer disease dementia (ADD), and are likely to additively alter the rate of decline or severity of cognitive impairment. The most important of these are Lewy body disease (LBD), TDP-43 proteinopathy and cerebrovascular disease, including white matter rarefaction (WMR) and cerebral infarcts. Comorbidities may interfere with ADD therapeutic trials evaluation of ADD clinical trials as they may not respond to AD-specific molecular therapeutics. It is possible, however, that at least some comorbidities may be, to some degree, secondary consequences of AD pathology, and if this were true then effective AD-specific therapeutics might also reduce the extent or severity of comorbid pathology. Comorbidities in ADD caused by autosomal dominant mutations such as those in the presenilin-1 (PSEN1) gene may provide an advantageous perspective on their pathogenesis, and deserve attention because these subjects are increasingly being entered into clinical trials. As ADD associated with PSEN1 mutations has a presumed single-cause etiology, and the average age at death is under 60, any comorbidities in this setting may be considered as at least partially secondary to the causative AD mechanisms rather than aging, and thus indicate whether effective ADD therapeutics may also be effective for comorbidities. In this study, we sought to compare the rates and types of ADD comorbidities between subjects with early-onset sporadic ADD (EOSADD; subjects dying under age 60) versus ADD associated with different types of PSEN1 mutations, the most common cause of early-onset autosomal dominant ADD. In particular, we were able to ascertain, for the first time, the prevalences of a fairly complete set of ADD comorbidities in United States (US) PSEN1 cases as well as the Colombian E280A PSEN1 kindred. Data for EOSADD and US PSEN1 subjects (with multiple different mutation types) was obtained from the National Alzheimer Coordinating Center (NACC). Colombian cases all had the E280A mutation and had a set of neuropathological observations classified, like the US cases according to the NACC NP10 definitions. Confirmatory of earlier reports, NACC-defined Alzheimer Disease Neuropathological Changes (ADNC) were consistently very severe in early-onset cases, whether sporadic or in PSEN1 cases, but were slightly less severe in EOSADD. Amyloid angiopathy was the only AD-associated pathology type with widely-differing severity scores between the 3 groups, with median scores of 3, 2 and 1 in the PSEN1 Colombia, PSEN1 US and EOSADD cases, respectively. Apoliprotein E genotype did not show significant proportional group differences for the possession of an E-4 or E-2 allele. Of ADD comorbidities, LBD was most common, being present in more than half of all cases in all 3 groups. For TDP-43 co-pathology, the Colombian PSEN1 group was the most affected, at about 27%, vs 16% and 11% for the US PSEN1 and sporadic US cases, respectively. Notably, hippocampal sclerosis and non-AD tau pathological conditions were not present in any of the US or Colombian PSEN1 cases, and was seen in only 3% of the EOSADD cases. Significant large-vessel atherosclerosis was present in a much larger percentage of Colombian PSEN1 cases, at almost 20% as compared to 0% and 3% of the US PSEN1 and EOSADD cases, respectively. Small-vessel disease, or arteriolosclerosis, was much more common than large vessel disease, being present in all groups between 18% and 37%. Gross and microscopic infarcts, however, as well as gross or microscopic hemorrhages, were generally absent or present at very low percentages in all groups. White matter rarefaction (WMR) was remarkably common, at almost 60%, in the US PSEN1 group, as compared to about 18% in the EOSADD cases, a significant difference. White matter rarefaction was not assessed in the Colombian PSEN1 cases. The results presented here, as well as other evidence, indicates that LBD, TDP-43 pathology and WMR, as common comorbidities with autosomal dominant and early-onset sporadic ADD, should be considered when planning clinical trials with such subjects as they may increase variability in response rates. However, they may be at least partially dependent on ADNC and thus potentially addressable by anti-amyloid or and/anti-tau therapies.Item LRRK2-associated parkinsonism with and without in vivo evidence of alpha-synuclein aggregates: longitudinal clinical and biomarker characterization(Oxford University Press, 2025-03-06) Chahine, Lana M.; Lafontant, David-Erick; Choi, Seung Ho; Iwaki, Hirotaka; Blauwendraat, Cornelis; Singleton, Andrew B.; Brumm, Michael C.; Alcalay, Roy N.; Merchant, Kalpana; Holohan Nudelman, Kelly Nicole; Dagher, Alain; Vo, Andrew; Tao, Qin; Venuto, Charles S.; Kieburtz, Karl; Poston, Kathleen L.; Bressman, Susan; Gonzalez-Latapi, Paulina; Avants, Brian; Coffey, Christopher; Jennings, Danna; Tolosa, Eduardo; Siderowf, Andrew; Marek, Ken; Simuni, Tatyana; Parkinson’s Progression Markers Initiative; Medical and Molecular Genetics, School of MedicineAmong LRRK2-associated parkinsonism cases with nigral degeneration, over two-thirds demonstrate evidence of pathologic alpha-synuclein, but many do not. Understanding the clinical phenotype and underlying biology in such individuals is critical for therapeutic development. Our objective was to compare clinical and biomarker features, and rate of progression over 4 years of follow-up, among LRRK2-associated parkinsonism cases with and without in vivo evidence of alpha-synuclein aggregates. Data were from the Parkinson's Progression Markers Initiative, a multicentre prospective cohort study. The sample included individuals diagnosed with Parkinson disease with pathogenic variants in LRRK2. Presence of CSF alpha-synuclein aggregation was assessed with seed amplification assay. A range of clinician- and patient-reported outcome assessments were administered. Biomarkers included dopamine transporter scan, CSF amyloid-beta1-42, total tau, phospho-tau181, urine bis(monoacylglycerol)phosphate levels and serum neurofilament light chain. Linear mixed-effects (LMMs) models examined differences in trajectory in CSF-negative and CSF-positive groups. A total of 148 LRRK2 parkinsonism cases (86% with G2019S variant), 46 negative and 102 positive for CSF alpha-synuclein seed amplification assay, were included. At baseline, the negative group was older than the positive group [median (inter-quartile range) 69.1 (65.2-72.3) versus 61.5 (55.6-66.9) years, P < 0.001] and a greater proportion were female [28 (61%) versus 43 (42%), P = 0.035]. Despite being older, the negative group had similar duration since diagnosis and similar motor rating scale [16 (11-23) versus 16 (10-22), P = 0.480] though lower levodopa equivalents. Only 13 (29%) of the negative group were hyposmic, compared with 75 (77%) of the positive group. The negative group, compared with the positive group, had higher per cent-expected putamenal dopamine transporter binding for their age and sex [0.36 (0.29-0.45) versus 0.26 (0.22-0.37), P < 0.001]. Serum neurofilament light chain was higher in the negative group compared with the positive group [17.10 (13.60-22.10) versus 10.50 (8.43-14.70) pg/mL; age-adjusted P-value = 0.013]. In terms of longitudinal change, the negative group remained stable in functional rating scale score in contrast to the positive group who had a significant increase (worsening) of 0.729 per year (P = 0.037), but no other differences in trajectory were found. Among individuals diagnosed with Parkinson disease with pathogenic variants in the LRRK2 gene, we found clinical and biomarker differences in cases without versus with in vivo evidence of CSF alpha-synuclein aggregates. LRRK2 parkinsonism cases without evidence of alpha-synuclein aggregates as a group exhibit less severe motor manifestations and decline. The underlying biology in LRRK2 parkinsonism cases without evidence of alpha-synuclein aggregates requires further investigation.Item MHCII reduction is insufficient to protect mice from alpha-synuclein-induced degeneration and the Parkinson's HLA locus exhibits epigenetic regulation(Springer Nature, 2025-04-21) Kline, Elizabeth M.; Jernigan, Janna E.; Scharer, Christopher D.; Maurer, Jeffrey; Hicks, Sakeenah L.; Herrick, Mary K.; Wallings, Rebecca L.; Kelly, Sean D.; Chang, Jianjun; Menees, Kelly B.; McFarland, Nikolaus R.; Boss, Jeremy M.; Tansey, Malú Gámez; Joers, Valerie; Neurology, School of MedicineMajor histocompatibility complex class II (MHCII) molecules are antigen presentation proteins and increased in post-mortem Parkinson's disease (PD) brain. Attempts to decrease MHCII expression have led to neuroprotection in PD mouse models. Our group reported that a single nucleotide polymorphism (SNP) at rs3129882 in the MHCII gene Human Leukocyte Antigen (HLA) DRA is associated with increased MHCII transcripts and surface protein and increased risk for late-onset idiopathic PD. We therefore hypothesized that decreased MHCII may mitigate dopaminergic degeneration. During an ongoing α-synuclein lesion, mice with MHCII reduction in systemic and brain innate immune cells (LysMCre + I-Abfl/fl or CRE+) displayed brain T cell repertoire shifts and greater preservation of the dopaminergic phenotype in nigrostriatal terminals. Next, we investigated a human cohort to characterize the immunophenotype of subjects with and without the high-risk GG genotype at the rs3129882 SNP. We confirmed that the high-risk GG genotype is associated with peripheral changes in MHCII inducibility, frequency of CD4 + T cells, and differentially accessible chromatin regions within the MHCII locus. Although our mouse studies indicate that myeloid MHCII reduction coinciding with an intact adaptive immune system is insufficient to fully protect dopamine neurons from α-synuclein-induced degeneration, our data are consistent with the overwhelming evidence implicating antigen presentation in PD pathophysiology.Item miRNAs and their putative roles in the development and progression of Parkinson's disease(Frontiers Media, 2013-01-09) Wong, Garry; Nass, Richard; Pharmacology and Toxicology, School of MedicineSmall regulatory RNAs, such as miRNAs, are increasingly being recognized not only as regulators of developmental processes but contributors to pathological states. The number of miRNAs determined experimentally to be involved in Parkinson's disease (PD) development and progression is small and includes regulators of pathologic proteins, neurotrophic factors, and xenobiotic metabolizing enzymes. PD gene-association studies have also indicated miRNAs in the pathology. In this review, we present known miRNAs and their validated targets that contribute to PD development and progression. We also incorporate data mining methods to link additional miRNAs with non-experimentally validated targets and propose additional roles of miRNAs in neurodegenerative processes. Furthermore, we present the potential contribution of next-generation-sequencing approaches to elucidate mechanisms and etiology of PD through discovery of novel miRNAs and other non-coding RNA classes.Item Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy(National Academy of Sciences, 2016-08-23) Bassil, Fares; Fernagut, Pierre-Olivier; Bezard, Erwan; Pruvost, Alain; Leste-Lasserre, Thierry; Hoang, Quyen Q.; Ringe, Dagmar; Petsko, Gregory A.; Meissner, Wassilios G.; Department of Biochemistry & Molecular Biology, IU School of MedicineMultiple system atrophy (MSA) is a sporadic orphan neurodegenerative disorder. No treatment is currently available to slow down the aggressive neurodegenerative process, and patients die within a few years after disease onset. The cytopathological hallmark of MSA is the accumulation of alpha-synuclein (α-syn) aggregates in affected oligodendrocytes. Several studies point to α-syn oligomerization and aggregation as a mediator of neurotoxicity in synucleinopathies including MSA. C-terminal truncation by the inflammatory protease caspase-1 has recently been implicated in the mechanisms that promote aggregation of α-syn in vitro and in neuronal cell models of α-syn toxicity. We present here an in vivo proof of concept of the ability of the caspase-1 inhibitor prodrug VX-765 to mitigate α-syn pathology and to mediate neuroprotection in proteolipid protein α-syn (PLP-SYN) mice, a transgenic mouse model of MSA. PLP-SYN and age-matched wild-type mice were treated for a period of 11 wk with VX-765 or placebo. VX-765 prevented motor deficits in PLP-SYN mice compared with placebo controls. More importantly, VX-765 was able to limit the progressive toxicity of α-syn aggregation by reducing its load in the striatum of PLP-SYN mice. Not only did VX-765 reduce truncated α-syn, but it also decreased its monomeric and oligomeric forms. Finally, VX-765 showed neuroprotective effects by preserving tyrosine hydroxylase-positive neurons in the substantia nigra of PLP-SYN mice. In conclusion, our results suggest that VX-765, a drug that was well tolerated in a 6 wk-long phase II trial in patients with epilepsy, is a promising candidate to achieve disease modification in synucleinopathies by limiting α-syn accumulation.Item A Review of Dementia with Lewy Bodies' Impact, Diagnostic Criteria and Treatment(Springer Nature, 2018-12) Capouch, Samuel D.; Farlow, Martin R.; Brosch, Jared R.; Neurology, School of MedicineDementia with Lewy bodies is one of the most common causes of dementia. It is not as common as Alzheimer's disease; the general public's awareness of the disease is poor in comparison. Its effects on caregivers and patients alike are not well known to the general population. There are currently no FDA-approved medications specifically for the treatment of DLB. Many of the medications that are approved for Alzheimer's disease are widely used in the treatment of DLB with varying degrees of success. Treatment of DLB is life long and requires a dedicated team of physicians and caregivers to minimize the degree of morbidity and mortality experienced by the patients suffering from the disease as it progresses.