Tetraspanin (TSP-17) Protects Dopaminergic Neurons against 6-OHDA-Induced Neurodegeneration in <i>C. elegans</i>

Parkinson's disease (PD), the second most prevalent neurodegenerative disease after Alzheimer's disease, is linked to the gradual loss of dopaminergic neurons in the substantia nigra. Disease loci causing hereditary forms of PD are known, but most cases are attributable to a combination of genetic and environmental risk factors. Increased incidence of PD is associated with rural living and pesticide exposure, and dopaminergic neurodegeneration can be triggered by neurotoxins such as 6-hydroxydopamine (6-OHDA). In C. elegans, this drug is taken up by the presynaptic dopamine reuptake transporter (DAT-1) and causes selective death of the eight dopaminergic neurons of the adult hermaphrodite. Using a forward genetic approach to find genes that protect against 6-OHDA-mediated neurodegeneration, we identified tsp-17, which encodes a member of the tetraspanin family of membrane proteins. We show that TSP-17 is expressed in dopaminergic neurons and provide genetic, pharmacological and biochemical evidence that it inhibits DAT-1, thus leading to increased 6-OHDA uptake in tsp-17 loss-of-function mutants. TSP-17 also protects against toxicity conferred by excessive intracellular dopamine. We provide genetic and biochemical evidence that TSP-17 acts partly via the DOP-2 dopamine receptor to negatively regulate DAT-1. tsp-17 mutants also have subtle behavioral phenotypes, some of which are conferred by aberrant dopamine signaling. Incubating mutant worms in liquid medium leads to swimming-induced paralysis. In the L1 larval stage, this phenotype is linked to lethality and cannot be rescued by a dop-3 null mutant. In contrast, mild paralysis occurring in the L4 larval stage is suppressed by dop-3, suggesting defects in dopaminergic signaling. In summary, we show that TSP-17 protects against neurodegeneration and has a role in modulating behaviors linked to dopamine signaling

A systematic review of biomarkers for disease progression in Parkinson's disease

Peer reviewedPublisher PD

Diffusion tensor imaging of Parkinson's disease, multiple system atrophy and progressive supranuclear palsy: a tract-based spatial statistics study

Although often clinically indistinguishable in the early stages, Parkinson's disease (PD), Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) have distinct neuropathological changes. The aim of the current study was to identify white matter tract neurodegeneration characteristic of each of the three syndromes. Tract-based spatial statistics (TBSS) was used to perform a whole-brain automated analysis of diffusion tensor imaging (DTI) data to compare differences in fractional anisotropy (FA) and mean diffusivity (MD) between the three clinical groups and healthy control subjects. Further analyses were conducted to assess the relationship between these putative indices of white matter microstructure and clinical measures of disease severity and symptoms. In PSP, relative to controls, changes in DTI indices consistent with white matter tract degeneration were identified in the corpus callosum, corona radiata, corticospinal tract, superior longitudinal fasciculus, anterior thalamic radiation, superior cerebellar peduncle, medial lemniscus, retrolenticular and anterior limb of the internal capsule, cerebral peduncle and external capsule bilaterally, as well as the left posterior limb of the internal capsule and the right posterior thalamic radiation. MSA patients also displayed differences in the body of the corpus callosum corticospinal tract, cerebellar peduncle, medial lemniscus, anterior and superior corona radiata, posterior limb of the internal capsule external capsule and cerebral peduncle bilaterally, as well as the left anterior limb of the internal capsule and the left anterior thalamic radiation. No significant white matter abnormalities were observed in the PD group. Across groups, MD correlated positively with disease severity in all major white matter tracts. These results show widespread changes in white matter tracts in both PSP and MSA patients, even at a mid-point in the disease process, which are not found in patients with PD

Risk of Parkinson disease in carriers of parkin mutations : estimation using the kin-cohort method

Objective: To estimate the risk of Parkinson disease (PD) in individuals with mutations in the Parkin gene. Design: We assessed point mutations and exon deletions and duplications in the Parkin gene in 247 probands with PD (age at onset 50 years) and 104 control probands enrolled in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. For each first-degree relative, a consensus diagnosis of PD was established. The probability that each relative carried a mutation was estimated from the proband's Parkin carrier status using Mendelian principles and from the relationship of the relative to the proband. Setting: Tertiary care movement disorders center. Patients: Cases, controls, and their first-degree relatives were enrolled in the GEPD study. Main Outcome Measures: Estimated age-specific penetrance in first-degree relatives. Results: Parkin mutations were identified in 25 probands with PD (10.1%), 18 (72.0%) of whom were heterozygotes. One Parkin homozygote was reported in 2 siblings with PD. The cumulative incidence of PD to age 65 years in carrier relatives (age-specific penetrance) was estimated to be 7.0% (95% confidence interval, 0.4%-71.9%), compared with 1.7% (95% confidence interval, 0.8%-3.4%) in noncarrier relatives of the cases (P = .59) and 1.1% (95% confidence interval, 0.3%-3.4%) in relatives of the controls (compared with noncarrier relatives, P = .52). Conclusions: The cumulative risk of PD to age 65 years in a noncarrier relative of a case with an age at onset of 50 years or younger is not significantly greater than the general population risk among controls. Age-specific penetrance among Parkin carriers, in particular heterozygotes, deserves further study. Mutations in the Parkin gene (PARK2; GenBank AB009973) are associated primarily with early-onset Parkinson disease (PD), defined as age at onset (AAO) ranging from 45 years or younger to 55 years or younger, but have also been described in PD cases with an AAO older than 70 years. In PD cases with an AAO of 45 years or younger with a mode of inheritance consistent with autosomal recessive transmission, the frequency of Parkin mutations may be as high as 49%, whereas in cases without a family history of PD the range is 15% to 18%. Age at onset is inversely correlated with the frequency of Parkin mutations in both familial and sporadic cases. Several studies have compared the AAO of PD in heterozygous, compound heterozygous, and homozygous Parkin mutation carriers and found that heterozygous cases, both familial and sporadic, have an older AAO. Heterozygous Parkin mutation carriers are more frequently reported among sporadic than familial cases. Information on the risk of PD in individuals who carry Parkin mutations in either the homozygous, compound heterozygous, or heterozygous state (or penetrance) is essential for genetic counseling. The penetrance of Parkin mutations has only been reported for isolated families. Most of the previous study designs sampled PD cases based on family history of PD, which would bias penetrance estimates upwards. To obtain an unbiased estimate of risk, a population-based random sample would be desirable, but Parkin mutations are so rare in the population that such a sample would have to be extremely large to obtain sufficient precision in penetrance estimates. To obtain unbiased estimates of the risk of PD in Parkin carriers despite the low population frequency of Parkin mutations, we used a kin-cohort study design applied to participants in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. The kin-cohort design is highly efficient for estimating penetrance because the relatives' mutation status is not required for the analyses, thus reducing costs for genetic analysis

Case-control study of the parkin gene in early-onset Parkinson disease

Background: Mutations in parkin are estimated to account for as much as 50% of familial Parkinson disease (PD) and 18% of sporadic PD. Single heterozygous mutations in parkin in both familial and sporadic cases may also increase susceptibility to PD. To our knowledge, all previous studies have been restricted to PD cases; this is the first study to systematically screen the parkin coding regions and exon deletions and duplications in controls. Objective: To determine the frequency and spectrum of parkin variants in early-onset PD cases (aged 50 years) and controls participating in a familial aggregation study. Patients and Methods: We sequenced the parkin gene in 101 cases and 105 controls. All cases and controls were also screened for exon deletions and duplications by semiquantitative multiplex polymerase chain reaction. Results: Thirteen (12.9% [95% confidence interval, 7%-21%]) of the 101 cases had a previously described parkin mutation: 1 was homozygous, 11 were heterozygous, and 1 was a compound heterozygote. The mutations Arg42Pro (exon 2) and Arg275Trp (exon 7) were recurrent. The previously reported synonymous substitution Leu261Leu (c.884A>G) was identified in 4 (3.9%) of 101 cases and 2 (2%) of 105 controls (P = .44). Excluding the synonymous substitution Leu261Leu (heterozygotes), 10 (9.9% [95% confidence interval, 4.6%-17.5%]) carried mutations. Conclusions: The frequency of mutations among cases that were not selected based on family history of PD is similar to what has previously been reported in sporadic PD. The similar frequency of Leu261Leu in cases and controls suggests it is a normal variant rather than a disease-associated mutation. We confirmed that heterozygous parkin mutations may increase susceptibility for early-onset PD

Cerebral activations related to ballistic, stepwise interrupted and gradually modulated movements in parkinson patients

Patients with Parkinson's disease (PD) experience impaired initiation and inhibition of movements such as difficulty to start/stop walking. At single-joint level this is accompanied by reduced inhibition of antagonist muscle activity. While normal basal ganglia (BG) contributions to motor control include selecting appropriate muscles by inhibiting others, it is unclear how PD-related changes in BG function cause impaired movement initiation and inhibition at single-joint level. To further elucidate these changes we studied 4 right-hand movement tasks with fMRI, by dissociating activations related to abrupt movement initiation, inhibition and gradual movement modulation. Initiation and inhibition were inferred from ballistic and stepwise interrupted movement, respectively, while smooth wrist circumduction enabled the assessment of gradually modulated movement. Task-related activations were compared between PD patients (N = 12) and healthy subjects (N = 18). In healthy subjects, movement initiation was characterized by antero-ventral striatum, substantia nigra (SN) and premotor activations while inhibition was dominated by subthalamic nucleus (STN) and pallidal activations, in line with the known role of these areas in simple movement. Gradual movement mainly involved antero-dorsal putamen and pallidum. Compared to healthy subjects, patients showed reduced striatal/SN and increased pallidal activation for initiation, whereas for inhibition STN activation was reduced and striatal-thalamo-cortical activation increased. For gradual movement patients showed reduced pallidal and increased thalamo-cortical activation. We conclude that PD-related changes during movement initiation fit the (rather static) model of alterations in direct and indirect BG pathways. Reduced STN activation and regional cortical increased activation in PD during inhibition and gradual movement modulation are better explained by a dynamic model that also takes into account enhanced responsiveness to external stimuli in this disease and the effects of hyper-fluctuating cortical inputs to the striatum and STN in particular

A combination of three surface modifiers for the optimal generation and application of natural hybrid nanopigments in a biodegradable resin

Our purpose was to improve the thermal, mechanical and optimal properties of an epoxy bioresin using optimum hybrid natural pigments previously synthesised in our lab. Next, we searched for the best combinations of factors in the synthesis of natural hybrid nanopigments and then incorporated them into the bioresin. We combined three structural modifiers in the nanopigment synthesis, surfactant, coupling agent (silane) and a mordant salt (alum), selected to replicate mordant textile dyeing with natural dyes. We used Taguchi s design L8 to seek final performance optimisation. We selected three natural dyes, chlorophyll, beta-carotene and beetroot extract, and used two laminar nanoclay types, montmorillonite and hydrotalcite. The thermal, mechanical and colorimetric characterisation of the composite obtained by mixing natural hybrid nanopigments (bionanocomposite) was made. The natural dye interactions with both nanoclays improved the thermal stabilities, colour performance and UV VIS light exposure stability of natural dyes and bioresins. The best bionanocomposite materials were found in an acidic pH [3, 4] environment and by modifying nanoclays with mordant and surfactant during the nanopigment synthesis processWe thank the Spanish Ministry of Economy and Competitiveness for funding Projects DPI2011-30090-C02-02 and DPI2015-68514-R.Micó Vicent, B.; Jordán Núñez, J.; Martinez Verdu, FM.; Balart Gimeno, RA. (2017). A combination of three surface modifiers for the optimal generation and application of natural hybrid nanopigments in a biodegradable resin. Journal of Materials Science. 52(2):889-898. https://doi.org/10.1007/s10853-016-0384-8S889898522Majdzadeh-Ardakani K, Nazari B (2010) Improving the mechanical properties of thermoplastic starch/poly(vinyl alcohol)/clay nanocomposites. 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Gene-Wise Association of Variants in Four Lysosomal Storage Disorder Genes in Neuropathologically Confirmed Lewy Body Disease

Objective Variants in GBA are associated with Lewy Body (LB) pathology. We investigated whether variants in other lysosomal storage disorder (LSD) genes also contribute to disease pathogenesis. Methods We performed a genetic analysis of four LSD genes including GBA, HEXA, SMPD1, and MCOLN1 in 231 brain autopsies. Brain autopsies included neuropathologically defined LBD without Alzheimer Disease (AD) changes (n = 59), AD without significant LB pathology (n = 71), Alzheimer disease and lewy body variant (ADLBV) (n = 68), and control brains without LB or AD neuropathology (n = 33). Sequencing of HEXA, SMPD1, MCOLN1 and GBA followed by ‘gene wise’ genetic association analysis was performed. To determine the functional effect, a biochemical analysis of GBA in a subset of brains was also performed. GCase activity was measured in a subset of brain samples (n = 64) that included LBD brains, with or without GBA mutations, and control brains. A lipidomic analysis was also performed in brain autopsies (n = 67) which included LBD (n = 34), ADLBV (n = 3), AD (n = 4), PD (n = 9) and control brains (n = 17), comparing GBA mutation carriers to non-carriers. Results In a ‘gene-wise’ analysis, variants in GBA, SMPD1 and MCOLN1 were significantly associated with LB pathology (p range: 0.03–4.14 x10-5). Overall, the mean levels of GCase activity were significantly lower in GBA mutation carriers compared to non-carriers (p<0.001). A significant increase and accumulation of several species for the lipid classes, ceramides and sphingolipids, was observed in LBD brains carrying GBA mutations compared to controls (p range: p<0.05-p<0.01). Interpretation Our study indicates that variants in GBA, SMPD1 and MCOLN1 are associated with LB pathology. Biochemical data comparing GBA mutation carrier to non-carriers support these findings, which have important implications for biomarker development and therapeutic strategies

A questionnaire-based (UM-PDHQ) study of hallucinations in Parkinson's disease

Background: Hallucinations occur in 20-40% of PD patients and have been associated with unfavorable clinical outcomes (i.e., nursing home placement, increased mortality). Hallucinations, like other non-motor features of PD, are not well recognized in routine primary/secondary clinical practice. So far, there has been no instrument for uniform characterization of hallucinations in PD. To this end, we developed the University of Miami Parkinson's disease Hallucinations Questionnaire (UM-PDHQ) that allows comprehensive assessment of hallucinations in clinical or research settings.Methods: The UM-PDHQ is composed of 6 quantitative and 14 qualitative items. For our study PD patients of all ages and in all stages of the disease were recruited over an 18-month period. The UPDRS, MMSE, and Beck Depression and Anxiety Inventories were used for comparisons.Results and Discussion: Seventy consecutive PD patients were included in the analyses. Thirty-one (44.3%) were classified as hallucinators and 39 as non-hallucinators. No significant group differences were observed in terms of demographics, disease characteristics, stage, education, depressive/anxiety scores or cognitive functioning (MMSE) between hallucinators and non-hallucinators. Single mode hallucinations were reported in 20/31 (visual/14, auditory/4, olfactory/2) whereas multiple modalities were reported in 11/31 patients. The most common hallucinatory experience was a whole person followed by small animals, insects and reptiles.Conclusion: Using the UM-PDHQ, we were able to define the key characteristics of hallucinations in PD in our cohort. Future directions include the validation of the quantitative part of the questionnaire than will serve as a rating scale for severity of hallucinations